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Binding Mode (binding + mode)
Kinds of Binding Mode Selected AbstractsThe Inorganic,Organic Hybrid Compound {[Mn(trien)]2SnS4}·4H2O: Exhibiting a Hitherto Unknown Binding Mode of the [SnS4]4, TetrahedronEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 12 2009Nicole Pienack Abstract The compound {[Mn(C6H18N4)]2SnS4}·4H2O (C6H18N4 = triethylenetetramine) was obtained under solvothermal conditions. In the structure of the {[Mn(C6H18N4)]2SnS4}, chain, two S atoms of the [SnS4]4, anion act in a hitherto never observed ,3 bridging mode that connects the Mn2S2N8 di-octahedra. The Mn2+ ions are octahedrally coordinated by four N and two S atoms, and two symmetry-related octahedra share a common S,S edge. Three of the H2O molecules are joined into chains through H-bonding interactions.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source] Bis(,-amine,borane) Complexes: An Unusual Binding Mode at a Transition-Metal Center,ANGEWANDTE CHEMIE, Issue 37 2009Romaeo Dallanegra Zweifaches Motiv: Bis(,-Aminboran)-Rhodium-Komplexe mit neuartigem Bindungsmotiv (zwei Aminboranliganden) wurden hergestellt (siehe Bild; Rh gelb, P grün, B rosa, N blau). Die Komplexe gehen Dehydrokupplungen unter Bildung von di- und trimeren cyclischen Aminoborylprodukten ein. [source] ChemInform Abstract: The Inorganic,Organic Hybrid Compound {[Mn(trien)]2SnS4}·4H2O: Exhibiting a Hitherto Unknown Binding Mode of the [SnS4]4- Tetrahedron.CHEMINFORM, Issue 29 2009Nicole Pienack Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Unexpected Novel Binding Mode of Pyrrolidine-Based Aspartyl Protease Inhibitors: Design, Synthesis and Crystal Structure in Complex with HIV ProteaseCHEMMEDCHEM, Issue 1 2006Edgar Specker Dr. Abstract At present nine FDA-approved HIV protease inhibitors have been launched to market, however rapid drug resistance arising under antiviral therapy calls upon novel concepts. Possible strategies are the development of ligands with less peptide-like character or the stabilization of a new and unexpected binding-competent conformation of the protein through a novel ligand-binding mode. Our rational design of pyrrolidinedimethylene diamines was inspired by the idea to incorporate key structural elements from classical peptidomimetics with a non-peptidic heterocyclic core comprising an endocyclic amino function to address the catalytic aspartic acid side chains of Asp,25 and 25,. The basic scaffolds were decorated by side chains already optimized for the recognition pockets of HIV protease or cathepsin,D. A multistep synthesis has been established to produce the central heterocycle and to give flexible access to side chain decorations. Depending on the substitution pattern of the pyrrolidine moiety, single-digit micromolar inhibition of HIV-1 protease and cathepsin,D has been achieved. Successful design is suggested in agreement with our modelling concepts. The subsequently determined crystal structure with HIV protease shows that the pyrrolidine moiety binds as expected to the pivotal position between both aspartic acid side chains. However, even though the inhibitors have been equipped symmetrically by polar acceptor groups to address the flap water molecule, it is repelled from the complex, and only one direct hydrogen bond is formed to the flap. A strong distortion of the flap region is detected, leading to a novel hydrogen bond which cross-links the flap loops. Furthermore, the inhibitor addresses only three of the four available recognition pockets. It achieves only an incomplete desolvation compared with the similarly decorated amprenavir. Taking these considerations into account it is surprising that the produced pyrrolidine derivatives achieve micromolar inhibition and it suggests extraordinary potency of the new compound class. Most likely, the protonated pyrrolidine moiety experiences strong enthalpic interactions with the enzyme through the formation of two salt bridges to the aspartic acid side chains. This might provide challenging opportunities to combat resistance of the rapidly mutating virus. [source] Bridging Binding Modes of Phosphine-Stabilized Nitrous Oxide to Zn(C6F5)2,ANGEWANDTE CHEMIE, Issue 51 2009Rebecca Auf der Jagd nach Dr. NNO: Die Reaktion von [tBu3PN2O(B(C6H4F)3)] mit 1, 1.5 oder 2,Äquivalenten Zn(C6F5)2 führt zu den Spezies [{tBu3PN2OZn(C6F5)2}2], [{tBu3PN2OZn(C6F5)2}2Zn(C6F5)2] bzw. [tBu3PN2O{Zn(C6F5)2}2] (siehe Struktur, rot Zn (große Kugel), O (kleine Kugel), grün N, gelb P), die einzigartige Bindungsweisen von Zn an das phosphanstabilisierte N2O-Fragment zeigen. [source] ChemInform Abstract: Interaction of Trivalent Lanthanide Cations with Nitrate Anions: A Quantum Chemical Investigation of Monodentate/Bidentate Binding Modes.CHEMINFORM, Issue 3 2002Marc Dobler Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] ChemInform Abstract: Structural Basis of Binding of High-Affinity Ligands to Protein Kinase C: Prediction of the Binding Modes Through a New Molecular Dynamics Method and Evaluation by Site-Directed Mutagenesis.CHEMINFORM, Issue 35 2001Youngshang Pak Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] The Role of C,H···H,B Interactions in Establishing Rotamer Configurations in Metallabis(dicarbollide) SystemsEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 16 2010Emilio José Juárez-Pérez Abstract The aim of this work is to explore the self-interaction capability of the anion [3,3,-Co(1,2-C2B9H11)2], through Ccluster,H···H,B (Cc,H···H,B) dihydrogen bonds. A set of theoretical and empirical data aiming to establish the main rules that account for the binding mode between the negatively charged borane framework made by [3,3,-Co(1,2-C2B9H11)2], and the [NMe4]+ ions have been compiled. The interaction between cation and anion is mainly electrostatic but the covalent contribution is also proven and quantified. The existing intermolecular H···H short contacts have been studied and are compared with available data from the Cambridge Structural Database. The results show that the electronic configuration of the transition metal atom in the sandwich complex is not enough to define the preferred rotamer due to the influence of the anion environment and the H···H interactions present in the solid state. We present a methodology with widely used theoretical tools to study cation···cobaltabisdicarbollide interactions in the solid state. [source] X-ray Crystal Structure of a Sodium Salt of [Gd(DOTP)]5,: Implications for Its Second-Sphere Relaxivity and the 23Na NMR Hyperfine Shift Effects of [Tm(DOTP)]5,EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 23 2003Fernando Avecilla Abstract The X-ray structure of the sodium salt of [Gd(DOTP)]5, shows two different chelates, [Gd(1)(DOTP)]5, and [Gd(2)(DOTP)]5,, bound at either surface of a sheet formed by a cluster of hydrated Na+ ions. Each [Gd(1)(DOTP)]5, anion binds directly to four Na+ ions of this cluster through the free oxygen atoms of the phosphonate groups of the adjacent ligand, while each [Gd(2)(DOTP)]5, unit is connected to the cluster via hydrogen bonds only. The Gd3+ ions in the two moieties do not have any inner-sphere water molecules, and are eight-coordinate. Their coordination polyhedra are twisted square antiprisms, with slightly different twist angles. These m, isomers are found in the crystal structure as racemic mixtures of enantiomers. Only one set of NMR resonances is observed in aqueous solution, corresponding to an averaged m, isomer. In this crystal structure, the Na+ ions bind the phosphonate oxygen atoms of the [Gd(1)(DOTP)]5, anion at positions far removed from the main symmetry axis. This is significantly different from the binding mode(s) previously proposed to be occurring in solution between Na+ and [Tm(DOTP)]5,, based on the interpretation of solution paramagnetic 23Na NMR shifts. This could arise as a result of the effects of the cluster of hydrated Na+ ions that are present, which may hinder axial binding modes and distort lateral binding modes. Further, in the crystal structure, both types of Gd3+ centers have four second-sphere water molecules that are located at distances (4.2,4.5 Å) significantly longer than those previously proposed from the analysis of the NMRD data of [Gd(1)(DOTP)]5,. This is a result of the coordination of Na+ by these water molecules, thus preventing their direct interaction with the phosphonate oxygen atoms. However, in solution such second-sphere water molecules can interact strongly with the phosphonate ligand oxygen atoms, resulting in efficient relaxation if their binding has relatively long lifetimes (> 50 ps). Rotational immobilization will amplify this contribution, thus making it similar to outer-sphere relaxation. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Molecular determinants of ligand specificity in family 11 carbohydrate binding modules , an NMR, X-ray crystallography and computational chemistry approachFEBS JOURNAL, Issue 10 2008Aldino Viegas The direct conversion of plant cell wall polysaccharides into soluble sugars is one of the most important reactions on earth, and is performed by certain microorganisms such as Clostridium thermocellum (Ct). These organisms produce extracellular multi-subunit complexes (i.e. cellulosomes) comprising a consortium of enzymes, which contain noncatalytic carbohydrate-binding modules (CBM) that increase the activity of the catalytic module. In the present study, we describe a combined approach by X-ray crystallography, NMR and computational chemistry that aimed to gain further insight into the binding mode of different carbohydrates (cellobiose, cellotetraose and cellohexaose) to the binding pocket of the family 11 CBM. The crystal structure of C. thermocellum CBM11 has been resolved to 1.98 Å in the apo form. Since the structure with a bound substrate could not be obtained, computational studies with cellobiose, cellotetraose and cellohexaose were carried out to determine the molecular recognition of glucose polymers by CtCBM11. These studies revealed a specificity area at the CtCBM11 binding cleft, which is lined with several aspartate residues. In addition, a cluster of aromatic residues was found to be important for guiding and packing of the polysaccharide. The binding cleft of CtCBM11 interacts more strongly with the central glucose units of cellotetraose and cellohexaose, mainly through interactions with the sugar units at positions 2 and 6. This model of binding is supported by saturation transfer difference NMR experiments and linebroadening NMR studies. [source] Structural and thermodynamic insights into the binding mode of five novel inhibitors of lumazine synthase from Mycobacterium tuberculosisFEBS JOURNAL, Issue 20 2006Ekaterina Morgunova Recently published genomic investigations of the human pathogen Mycobacterium tuberculosis have revealed that genes coding the proteins involved in riboflavin biosynthesis are essential for the growth of the organism. Because the enzymes involved in cofactor biosynthesis pathways are not present in humans, they appear to be promising candidates for the development of therapeutic drugs. The substituted purinetrione compounds have demonstrated high affinity and specificity to lumazine synthase, which catalyzes the penultimate step of riboflavin biosynthesis in bacteria and plants. The structure of M. tuberculosis lumazine synthase in complex with five different inhibitor compounds is presented, together with studies of the binding reactions by isothermal titration calorimetry. The inhibitors showed the association constants in the micromolar range. The analysis of the structures demonstrated the specific features of the binding of different inhibitors. The comparison of the structures and binding modes of five different inhibitors allows us to propose the ribitylpurinetrione compounds with C4,C5 alkylphosphate chains as most promising leads for further development of therapeutic drugs against M. tuberculosis. [source] Exploring the GluR2 ligand-binding core in complex with the bicyclical AMPA analogue (S)-4-AHCPFEBS JOURNAL, Issue 7 2005Bettina B. Nielsen The X-ray structure of the ionotropic GluR2 ligand-binding core (GluR2-S1S2J) in complex with the bicyclical AMPA analogue (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H -cyclohepta[d]-4-isoxazolyl)propionic acid [(S)-4-AHCP] has been determined, as well as the binding pharmacology of this construct and of the full-length GluR2 receptor. (S)-4-AHCP binds with a glutamate-like binding mode and the ligand adopts two different conformations. The Ki of (S)-4-AHCP at GluR2-S1S2J was determined to be 185 ± 29 nm and at full-length GluR2(R)o it was 175 ± 8 nm. (S)-4-AHCP appears to elicit partial agonism at GluR2 by inducing an intermediate degree of domain closure (17°). Also, functionally (S)-4-AHCP has an efficacy of 0.38 at GluR2(Q)i, relative to (S)-glutamate. The proximity of bound (S)-4-AHCP to domain D2 prevents full D1,D2 domain closure, which is limited by steric repulsion, especially between Leu704 and the ligand. [source] Exploring the primary electron acceptor (QA)-site of the bacterial reaction center from Rhodobacter sphaeroidesFEBS JOURNAL, Issue 4 2002Binding mode of vitamin K derivatives The functional replacement of the primary ubiquinone (QA) in the photosynthetic reaction center (RC) from Rhodobacter sphaeroides with synthetic vitamin K derivatives has provided a powerful tool to investigate the electron transfer mechanism. To investigate the binding mode of these quinones to the QA binding site we have determined the binding free energy and charge recombination rate from QA, to D+ (kAD) of 29 different 1,4-naphthoquinone derivatives with systematically altered structures. The most striking result was that none of the eight tested compounds carrying methyl groups in both positions 5 and 8 of the aromatic ring exhibited functional binding. To understand the binding properties of these quinones on a molecular level, the structures of the reaction center-naphthoquinone complexes were predicted with ligand docking calculations. All protein,ligand structures show hydrogen bonds between the carbonyl oxygens of the quinone and AlaM260 and HisM219 as found for the native ubiquinone-10 in the X-ray structure. The center-to-center distance between the naphthoquinones at QA and the native ubiquinone-10 at QB (the secondary electron acceptor) is essentially the same, compared to the native structure. A detailed analysis of the docking calculations reveals that 5,8-disubstitution prohibits binding due to steric clashes of the 5-methyl group with the backbone atoms of AlaM260 and AlaM249. The experimentally determined binding free energies were reproduced with an rmsd of ,,4 kJ·mol,1 in most cases providing a valuable tool for the design of new artificial electron acceptors and inhibitors. [source] Sensitized Lanthanide-Ion Luminescence with Aryl-Substituted N -(2-Nitrophenyl)acetamide-Derived ChromophoresHELVETICA CHIMICA ACTA, Issue 11 2009Michael Andrews Abstract The syntheses of the two tetraazamacrocyclic ligands L1 and L2 bearing a [(methoxy-2-nitrophenyl)amino]carbonyl chromophore, i.e., an N -(methoxy-2-nitrophenyl)acetamide moiety, together with their corresponding lanthanide-ion complexes are described. A combined spectroscopic (UV/VIS, 1H-NMR), structural (X-ray), and theoretical (DFT) investigation revealed that the absorption properties of the chromophores were dictated by the extent of electronic delocalisation, which in turn was determined by the position of the MeO substituent at the aromatic ring. X-Ray crystallographic studies showed that when attached to the macrocycle, both isomeric forms of the N -(methoxy-2-nitrophenyl)acetamide unit can participate in coordination, via the CO, to an encapsulated potassium cation. Luminescence measurements confirmed that such a binding mode also exists in solution for the corresponding lanthanide complexes (q ca. ,1), with the para -MeO derivative allowing longer wavelength sensitization (,ex 330,nm). [source] Stability of Hoogsteen -Type Triplexes , Electrostatic Attraction between Duplex Backbone and Triplex-Forming Oligonucleotide (TFO) Using an Intercalating ConjugateHELVETICA CHIMICA ACTA, Issue 5 2008Daniel Globisch Abstract Syntheses are described for two novel twisted intercalating nucleic acid (TINA) monomers where the intercalator comprises a benzene ring linked to a naphthalimide moiety via an ethynediyl bridge. The intercalators Y and Z have a 2-(dimethylamino)ethyl and a methyl residue on the naphthalimide moiety, respectively. When used as triplex-forming oligonucleotides (TFOs), the novel naphthalimide TINAs show extraordinary high thermal stability in Hoogsteen -type triplexes and duplexes with high discrimination of mismatch strands. DNA Strands containing the intercalator Y show higher thermal triplex stability than DNA strands containing the intercalator Z. This observation can be explained by the ionic interaction of the protonated dimethylamino group under physiological conditions, targeting the negatively charged phosphate backbone of the duplex. This interaction leads to an extra binding mode between the TFO and the duplex, in agreement with molecular-modeling studies. We believe that this is the first example of an intercalator linking the TFO to the phosphate backbone of the duplex by an ionic interaction, which is a promising tool to achieve a higher triplex stability. [source] On the binding mode of urease active site inhibitors: A density functional studyINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 11 2008M. Leopoldini Abstract The way with which boric acid, a rapid reversible competitive inhibitor, binds the urease active site was explored at density functional B3LYP level of theory. The catalytic core of the enzyme was simulated by two models of different size. In both cases, amino acid residues belonging to the inner and to the outer coordination spheres of nickel ions were replaced by smaller molecular species. Contrary to the experimental indication that attributes the inhibitory ability of this acid to the lack of a nucleophilic attack by the enzyme to the boron atom, we instead found that another possibility exists based on the presence of a strong covalent , bond between boron and urease that we think can be hardly broken to allow any course of the reaction. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008 [source] Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantumJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 13 2010Santhosh Kannan Venkatesan Abstract Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol-redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9-aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9-aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] A combined molecular modeling study on gelatinases and their potent inhibitorsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2010Lili Xi Abstract Zinc-dependent matrix metalloproteinase (MMP) family is considered to be an attractive target because of its important role in many physiological and pathological processes. In the present work, a molecular modeling study combining protein-, ligand- and complex-based computational methods was performed to analyze a new series of ,- N -biaryl ether sulfonamide hydroxamates as potent inhibitors of gelatinase A (MMP-2) and gelatinase B (MMP-9). Firstly, the similarities and differences between the binding sites of MMP-2 and MMP-9 were analyzed through sequence alignment and structural superimposition. Secondly, in order to extract structural features influencing the activities of these inhibitors, quantitative structure-activity relationship (QSAR) models using genetic algorithm-multiple linear regression (GA-MLR), comparative molecular field (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed. The proposed QSAR models could give good predictive ability for the studied inhibitors. Thirdly, docking study was employed to further explore the binding mode between the ligand and protein. The results from all the above analyses could provide the information about the similarities and differences of the binding mode between the MMP-2, MMP-9 and their potent inhibitors. The obtained results can provide very useful information for the design of new potential inhibitors. © 2009 Wiley Periodicals, Inc. J Comput Chem 2010 [source] Stereoelectronic properties of spiroquinazolinones in differential PDE7 inhibitory activityJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 12 2008Pankaj R. Daga Abstract A detailed computational study on a series of spiroquinazolinones showing phosphodiesterase 7 (PDE7) inhibitory activity was performed to understand the binding mode and the role of stereoelectronic properties in binding. Our docking studies reproduced the essential hydrogen bonding and hydrophobic interactions for inhibitors of this class of enzymes. The N1 proton of the quinazolinone scaffold was involved in H-bonding to an amide side chain of the conserved glutamine residue in the active site. The central bicyclic ring of the molecules showed hydrophobic and ,-stacking interactions with hydrophobic and aromatic amino acid residues, respectively, present in the PDE7 active site. The docked conformations were optimized with density functional theory (DFT) and DFT electronic properties were calculated. Comparison of molecular electrostatic potential (MEP) plots of inhibitors with the active site of PDE7 suggested that the electronic distribution in the molecules is as important as steric factors for binding of the molecules to the receptor. The hydrogen bonding ability and nucleophilic nature of N1 appeared to be important for governing the interaction with PDE7. For less active inhibitors (pIC50 < 6.5), the MEP maximum at N1 of the spiroquinazolinone ring was high or low based on the electronic properties of the substituents. All the more active molecules (pIC50 > 6.5) had MEP highest at N3, not N1. Efficient binding of these inhibitors may need some rearrangement of side chains of active-site residues, especially Asn365. This computational modeling study should aid in design of new molecules in this class with improved PDE7 inhibition. © 2008 Wiley Periodicals, Inc. J Comput Chem 2008 [source] Evaluation of relative DNA binding affinities of anthrapyrazoles by electrospray ionization mass spectrometryJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 5 2007Suncerae I. Smith Abstract Binding interactions of a new series of anthrapyrazoles (APs) with DNA were evaluated by electrospray ionization mass spectrometry (ESI-MS). Relative binding affinities were estimated from the ESI-MS data based on the fraction of bound DNA for DNA/anthrapyrazole mixtures, and they show a correlation to the shift in melting point of the DNA measured from a previous study. Minimal sequence specificity was observed for the series of anthrapyrazoles. Upon collisionally activated dissociation of the duplex/anthrapyrazole complexes, typically ejection of the ligand was the dominant pathway for most of the complexes. However, for complexes containing AP2 or mitoxantrone, strand separation with the ligand remaining on one of the single strands was observed, indicative of a different binding mode or stronger binding. Copyright © 2007 John Wiley & Sons, Ltd. [source] The Single-Stranded DNA- and RNA-Binding Proteins Pur , and Pur , Link BC1 RNA to Microtubules Through Binding to the Dendrite-Targeting RNA MotifsJOURNAL OF NEUROCHEMISTRY, Issue 5 2000Sachiyo Ohashi Abstract: Neural BC1 RNA is distributed in neuronal dendrites as RNA,protein complexes (BC1 RNPs) containing Translin. In this study, we demonstrated that the single-stranded DNA- and RNA-binding protein pur , and its isoform, pur ,, which have been implicated in control of DNA replication and transcription, linked BC1 RNA to microtubules (MTs). The binding site was within the 5, proximal region of BC1 RNA containing putative dendrite-targeting RNA motifs rich in G and U residues, suggesting that in the cytoplasm of neurons, these nuclear factors are involved in the BC1 RNA transport along dendritic MTs. The pur proteins were not components of BC1 RNP but appeared to associate with MTs in brain cells. Therefore, it is suggested that they may transiently interact with the RNP during transport. In this respect, the interaction of pur proteins with BC1 RNA could be regulated by the Translin present within the RNP, because the binding mode of these two classes of proteins (pur proteins and Translin) to the dendrite-targeting RNA motifs was mutually exclusive. As the motifs are well conserved in microtubule-associated protein 2a/b mRNA as well, the pur proteins may also play a role(s) in the dendritic transport of a subset of mRNAs. [source] Substituent effects of phthalimide-based nucleoside analogs on binding a CG Watson,Crick base pairJOURNAL OF PHYSICAL ORGANIC CHEMISTRY, Issue 10 2007Z. Xiao Abstract Five differently substituted phthalimide nucleosides were studied by NMR spectroscopic techniques for their ability to recognize and bind a cytosine,guanosine (CG) Watson,Crick base pair in CD2Cl2. Whereas only rather weak binding was observed for analogs with an amino, acetamido, or benzamido substituent, strong binding was observed with the analogs carrying an ureido and n -butyl ureido residue. 2D NOE measurements at low temperatures confirm the proposed binding mode for the high-affinity ligands but indicate binding interactions for the weakly bound analogs different from the expected geometry. Copyright © 2007 John Wiley & Sons, Ltd. [source] Characteristic Raman and IR bands of 3,3,-benzylidenebis(4-hydroxycoumarin) and its La(III), Ce(III) and Nd(III) complexesJOURNAL OF RAMAN SPECTROSCOPY, Issue 8 2006N. Trendafilova Abstract In the present paper we perform a detailed vibrational study of 3,3,-benzylidenebis(4-hydroxycoumarin) (phenyldicoumarol, PhDC) based on both experimental (IR and Raman) and calculated (DFT) vibrational spectra. To help the assignment of the PhDC vibrational modes, the vibrational spectrum of the monomeric building block, 4-hydroxycoumarin (4-HC), was also considered. The PhDC and 4-HC vibrational spectra were calculated and assigned at the B3LYP/6-31G* optimized geometries. The vibrational spectra of the La(III), Ce(III) and Nd(III) complexes with PhDC are discussed in a comparative study with the vibrational spectrum of the free PhDC ligand. The ,(CCH)ip, ,(CCH)op and ,(COH)ip vibrational modes as well as in-plane phenyl- and in-plane coumarin rings deformations were observed as strong bands in the Raman spectrum of PhDC and can be considered as a characteristic for the compound. Because of the very low IR intensity, these modes were not detected in the IR spectrum. Informative ligand vibrational modes were selected and their behaviors in the Ln(III) complexes were further studied to suggest the type of the PhDC binding mode to Ln(III) ions. Copyright © 2006 John Wiley & Sons, Ltd. [source] Thermodynamic origin of the chiral recognition of tryptophan on teicoplanin and teicoplanin aglycone stationary phasesJOURNAL OF SEPARATION SCIENCE, JSS, Issue 5 2005Mohamed Haroun Abstract The D-, L-tryptophan binding and the chiral recognition properties of the teicoplanin and teicoplanin aglycone (TAG) chiral stationary phase (CSPs) were compared at various column temperatures. The solute adsorption isotherms (bi-Langmuir model) were determined for both the two CSPs using the perturbation method. It was demonstrated that the sugar units were involved in the reduction of the apparent enantioselectivity through two phenomena: (i) the inhibition of some enantioselective contacts with low-affinity binding regions of the aglycone and (ii) a decrease in the stereoselective properties of the aglycone high-affinity binding pocket. The phenomenon (ii) was governed by both a decrease in the ratio of the enantiomer adsorption constant and a strong reduction of the site accessibility for D- and L-tryptophan. In addition, a temperature effect study was performed to investigate the chiral recognition mechanism at the aglycone high-affinity pocket. An enthalpy-entropy compensation analysis derived from the Grunwald model as well as the comparison with the literature data demonstrated that the enantioselective binding mode was dependent on an interface dehydration process. The change in the enantioselective process observed between the TAG and teicoplanin CSP was characterized by a difference of ca. 2,3 ordered water molecules released from the species interface. [source] Cellulosomes: microbial nanomachines that display plasticity in quaternary structureMOLECULAR MICROBIOLOGY, Issue 6 2007Harry J. Gilbert Summary The assembly of proteins that display complementary activities into supramolecular intra- and extracellular complexes is central to cellular function. One such nanomachine of considerable biological and industrial significance is the plant cell wall degrading apparatus of anaerobic bacteria termed the cellulosome. The Clostridium thermocellum cellulosome assembles through the interaction of a type I dockerin module in the catalytic entities with one of several type I cohesin modules in the non-catalytic scaffolding protein. Recent structural studies have provided the molecular details of how dockerin,cohesin interactions mediate both cellulosome assembly and the retention of the protein complex on the bacterial cell surface. The type I dockerin, which displays near-perfect sequence and structural symmetry, interacts with its cohesin partner through a dual binding mode in which either the N- or C-terminal helix dominate heterodimer formation. The biological significance of this dual binding mode is discussed with respect to the plasticity of the orientation of the catalytic subunits within this supramolecular assembly. The flexibility in the quaternary structure of the cellulosome may reflect the challenges presented by the degradation of a heterogenous recalcitrant insoluble substrate by an intricate macromolecular complex, in which the essential synergy between the catalytic subunits is a key feature of cellulosome function. [source] Unusual binding interactions in PDZ domain crystal structures help explain binding mechanismsPROTEIN SCIENCE, Issue 4 2010Jonathan M. Elkins Abstract PDZ domains most commonly bind the C-terminus of their protein targets. Typically the C-terminal four residues of the protein target are considered as the binding motif, particularly the C-terminal residue (P0) and third-last residue (P-2) that form the major contacts with the PDZ domain's "binding groove". We solved crystal structures of seven human PDZ domains, including five of the seven PDLIM family members. The structures of GRASP, PDLIM2, PDLIM5, and PDLIM7 show a binding mode with only the C-terminal P0 residue bound in the binding groove. Importantly, in some cases, the P-2 residue formed interactions outside of the binding groove, providing insight into the influence of residues remote from the binding groove on selectivity. In the GRASP structure, we observed both canonical and noncanonical binding in the two molecules present in the asymmetric unit making a direct comparison of these binding modes possible. In addition, structures of the PDZ domains from PDLIM1 and PDLIM4 also presented here allow comparison with canonical binding for the PDLIM PDZ domain family. Although influenced by crystal packing arrangements, the structures nevertheless show that changes in the positions of PDZ domain side-chains and the ,B helix allow noncanonical binding interactions. These interactions may be indicative of intermediate states between unbound and fully bound PDZ domain and target protein. The noncanonical "perpendicular" binding observed potentially represents the general form of a kinetic intermediate. Comparison with canonical binding suggests that the rearrangement during binding involves both the PDZ domain and its ligand. [source] Thermodynamic characterization of two homologous protein complexes: Associations of the semaphorin receptor plexin-B1 RhoGTPase binding domain with Rnd1 and active Rac1PROTEIN SCIENCE, Issue 5 2009Prasanta K. Hota Abstract Plexin receptors function in response to semaphorin guidance cues in a variety of developmental processes involving cell motility. Interactions with Rho, as well as Ras family small GTPases are critical events in the cell signaling mechanism. We have recently determined the structure of a cytoplasmic domain (RBD) of plexin-B1 and mapped its binding interface with several Rho-GTPases, Rac1, Rnd1, and RhoD. All three GTPases associate with a similar region of this plexin domain, but show different functional behavior in cells. To understand whether thermodynamic properties of the GTPase,RBD interaction contribute to such different behavior, we have examined the interaction at different temperatures, buffer, and pH conditions. Although the binding affinity of both Rnd1 and Rac1 with the plexin-B1 RBD is similar, the detailed thermodynamic properties of the interactions are considerably different. These data suggest that on Rac1 binding to the plexin-B1 RBD, the proteins become more rigid in the complex. By contrast, Rnd1 binding is consistent with unchanged or slightly increased flexibility in one or both proteins. Both GTPases show an appreciable reduction in affinity for the dimeric plexin-B1 RBD indicating that GTPase binding is not cooperative with dimer formation, but that a partial steric hindrance destabilizes the dimer. However, a reduced affinity binding mode to a disulphide stabilized model for the dimeric RBD is also possible. Consistent with cellular studies, the interaction thermodynamics imply that further levels of regulation involving additional binding partners and/or regions outside of the RhoGTPase binding domain are required for receptor activation. [source] Crystal structure of enoyl,acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitorPROTEIN SCIENCE, Issue 4 2008Jun Saito Abstract Enoyl,acyl carrier protein (ACP) reductases are critical for bacterial type II fatty acid biosynthesis and thus are attractive targets for developing novel antibiotics. We determined the crystal structure of enoyl,ACP reductase (FabK) from Streptococcus pneumoniae at 1.7 Å resolution. There was one dimer per asymmetric unit. Each subunit formed a triose phosphate isomerase (TIM) barrel structure, and flavin mononucleotide (FMN) was bound as a cofactor in the active site. The overall structure was similar to the enoyl,ACP reductase (ER) of fungal fatty acid synthase and to 2-nitropropane dioxygenase (2-ND) from Pseudomonas aeruginosa, although there were some differences among these structures. We determined the crystal structure of FabK in complex with a phenylimidazole derivative inhibitor to envision the binding site interactions. The crystal structure reveals that the inhibitor binds to a hydrophobic pocket in the active site of FabK, and this is accompanied by induced-fit movements of two loop regions. The thiazole ring and part of the ureido moiety of the inhibitor are involved in a face-to-face ,,, stacking interaction with the isoalloxazine ring of FMN. The side-chain conformation of the proposed catalytic residue, His144, changes upon complex formation. Lineweaver,Burk plots indicate that the inhibitor binds competitively with respect to NADH, and uncompetitively with respect to crotonoyl coenzyme A. We propose that the primary basis of the inhibitory activity is competition with NADH for binding to FabK, which is the first step of the two-step ping-pong catalytic mechanism. [source] Characterization of an exosite binding inhibitor of matrix metalloproteinase 13PROTEIN SCIENCE, Issue 1 2008Lata T. Gooljarsingh Abstract Matrix metalloproteinase 13 (MMP13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis. Clinical administration of broad spectrum MMP inhibitors such as marimastat has been implicated in severe musculo-skeletal side effects. Consequently, research has been focused on designing inhibitors that selectively inhibit MMP13, thereby circumventing musculo-skeletal toxicities. A series of pyrimidine dicarboxamides were recently shown to be highly selective inhibitors of MMP13 with a novel binding mode. We have applied a molecular ruler to this exosite by dual inhibition studies involving a potent dicarboxamide in the presence of two metal chelators of different sizes. A larger hydroxamate mimic overlaps and antagonizes binding of the dicarboxamide to the exosite whereas the much smaller acetohydroxamate synergizes with the dicarboxamide. These studies elucidate the steric requirement for compounds that fit exclusively into the active site, a mandate for generating highly selective MMP13 inhibitors. [source] Solution structure of GOPC PDZ domain and its interaction with the C-terminal motif of neuroliginPROTEIN SCIENCE, Issue 9 2006Xiang Li Abstract GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein) represents a PDZ domain-containing protein associated with the Golgi apparatus, which plays important roles in vesicular trafficking in secretory and endocytic pathways. GOPC interacts with many other proteins, such as the Wnt receptors Frizzled 8 and neuroligin via its PDZ domain. Neuroligin is a neural cell-adhesion molecule of the post-synapse, which binds to the presynapse molecule neurexin to form a heterotypic intercellular junction. Here we report the solution structure of the GOPC PDZ domain by NMR. Our results show that it is a canonical class I PDZ domain, which contains two ,-helices and six ,-strands. Using chemical shift perturbation experiments, we further studied the binding properties of the GOPC PDZ domain with the C-terminal motif of neuroligin. The observations showed that the ensemble of the interaction belongs to fast exchange with low affinity. The 3D model of the GOPC PDZ domain/neuroligin C-terminal peptide complex was constructed with the aid of the molecular dynamics simulation method. Our discoveries provide insight into the specific interaction of the GOPC PDZ domain with the C-terminal peptide of Nlg and also provide a general insight about the possible binding mode of the interaction of Nlg with other PDZ domain-containing proteins. 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