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Extended Conformation (extended + conformation)
Selected AbstractsGlobal physicochemical properties as activity discriminants for the mGluR1 subtype of metabotropic glutamate receptorsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 16 2001Marta Filizola Abstract Metabotropic glutamate receptors (mGluRs) are important as candidate therapeutic targets for many neurological disorders. In the present work, the focus has been on the mGluR1 subtype, where agonists have a proconvulsant profile while antagonists exert anticonvulsant activity. Identification of molecular determinants for the inhibition of mGluR1 provides a new avenue for the discovery and development of novel anticonvulsant drugs. Spatial configuration of key groups alone cannot explain activation selectivity at this specific receptor subtype. In fact, all known agonists and antagonists acting at mGluR1 can accommodate the same critical moieties in a similar geometric arrangement that corresponds to the extended conformation of glutamate. Therefore, other factors must account for the differences in activation. This study presents the results of an analysis of a large suite of steric, topological, electrostatic, and thermodynamic molecular properties calculated for a representative set of potent mGluR1 agonists and antagonists. Global steric parameters and the total nonpolar area provide discrimination between the mGluR1 agonists and antagonists considered in the present work. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 2018,2027, 2001 [source] CD247 can bind SHC1, no matter if CD247 is phosphorylatedJOURNAL OF MOLECULAR RECOGNITION, Issue 3 2009Tao Liu Abstract On T cell receptor (TCR) stimulation, src homology 2 domain-containing transforming protein C1 (SHC1) had been found to bind the tyrosine-phosphorylated CD247 chain of the receptor via its src homology 2 (SH2) domain, delivering signals that control T cell development and activation. However, how the phosphorylation of CD247 led to the instant binding has not been characterized clearly. To study the binding process in detail, we simulated and compared the interaction processes of the SH2 domain with CD247 and phosphorylated CD247, respectively. Unexpectedly, the simulation revealed that SHC1 can also bind the nonphosphorylated CD247 peptide, which was further validated to be a weak binding by affinity pull-down experiment. The molecular dynamics (MD) simulation also revealed that the CD247 peptide formed a folding conformation with its Leu209 inserted into the hydrophobic binding pocket in SHC1. And on phosphorylation, it was the electrostatic attraction between the CD247 Tyr(P)206 and the SHC1 Tyr(P)-binding pocket that destroyed the folding conformation of the nonphosphorylated CD247 and, aided by the electrostatic attraction between SHC1 and the Asp203 of CD247, led to the extended conformation of the phosphorylated CD247 binding to SHC1 strongly. The results suggest that nonphosphorylated CD247 can recruit SHC1 in advance to prepare for the instant needs for SHC1 on TCR stimulation. In view of the ubiquity of phosphorylation in protein interaction regulation, we think this study also exemplified the usefulness of MD in more interactome research involving phosphorylation. Copyright © 2009 John Wiley & Sons, Ltd. [source] Self-assembling properties of ionic-complementary peptides,JOURNAL OF PEPTIDE SCIENCE, Issue 3 2009Gabriella D'Auria Abstract Self-complementary synthetic peptides, composed by 8 and 16 residues, were analyzed by CD, NMR and small angle neutron scattering (SANS) techniques in order to investigate the relevance of charge and hydrophobic interactions in determining their self-assembling properties. All the sequences are potentially able to form fibrils and membranes as they share, with the prototype EAK16, a strictly alternating arrangement of polar and nonpolar residues. We find that 16-mer peptides show higher self-assembling propensities than the 8-mer analogs and that the aggregation processes are favored by salts and neutral pH. Peptide hydrophobic character appears as the most relevant factor in determining self-assembling. Solution conformational analysis, diffusion and SANS measurements all together show that the sequences with a higher self-assemble propensity are distributed, in mild conditions, between light and heavy forms. For some of the systems, the light form is mostly constituted by monomers in a random conformation, while the heavy one is constituted by ,-aggregates. In our study we also verified that sequences designed to adopt extended conformation, when dissolved in alcohol-water mixtures, can easily fold in helix structures. In that media, the prototype of the series appears distributed between helical monomers and ,-aggregates. It is worth noticing that the structural conversion from helical monomer to ,-aggregates, mimics ,-amyloid peptide aggregation mechanisms. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd. [source] ,-Hairpin folding and stability: molecular dynamics simulations of designed peptides in aqueous solutionJOURNAL OF PEPTIDE SCIENCE, Issue 9 2004Clara M. Santiveri Abstract The structural properties of a 10-residue and a 15-residue peptide in aqueous solution were investigated by molecular dynamics simulation. The two designed peptides, SYINSDGTWT and SESYINSDGTWTVTE, had been studied previously by NMR at 278 K and the resulting model structures were classified as 3:5 ,-hairpins with a type I + G1 ,-bulge turn. In simulations at 278 K, starting from the NMR model structure, the 3:5 ,-hairpin conformers proved to be stable over the time period evaluated (30 ns). Starting from an extended conformation, simulations of the decapeptide at 278 K, 323 K and 353 K were also performed to study folding. Over the relatively short time scales explored (30 ns at 278 K and 323 K, 56 ns at 353 K), folding to the 3:5 ,-hairpin could only be observed at 353 K. At this temperature, the collapse to ,-hairpin-like conformations is very fast. The conformational space accessible to the peptide is entirely dominated by loop structures with different degrees of ,-hairpin character. The transitions between different types of ordered loops and ,-hairpins occur through two unstructured loop conformations stabilized by a single side-chain interaction between Tyr2 and Trp9, which facilitates the changes of the hydrogen-bond register. In agreement with previous experimental results, ,-hairpin formation is initially driven by the bending propensity of the turn segment. Nevertheless, the fine organization of the turn region appears to be a late event in the folding process. Copyright © 2004 European Peptide Society and John Wiley & Sons, Ltd. [source] Binding interactions between peptides and proteins of the class II Major Histocompatibility ComplexMEDICINAL RESEARCH REVIEWS, Issue 2 2002Benjamin J. McFarland Abstract The activation of helper T cells by peptides bound to proteins of the class II Major Histocompatibility Complex (MHC II) is pivotal to the initiation of an immune response. The primary functional requirement imposed on MHC II proteins is the ability to efficiently bind thousands of different peptides. Structurally, this is reflected in a unique architecture of binding interactions. The peptide is bound in an extended conformation within a groove on the membrane distal surface of the protein that is lined with several pockets that can accommodate peptide side-chains. Conserved MHC II protein residues also form hydrogen bonds along the length of the peptide main-chain. Here we review recent advances in the study of peptide-MHC II protein reactions that have led to an enhanced understanding of binding energetics. These results demonstrate that peptide-MHC II protein complexes achieve high affinity binding from the array of hydrogen bonds that are energetically segregated from the pocket interactions, which can then add to an intrinsic hydrogen bond-mediated affinity. Thus, MHC II proteins are unlike antibodies, which utilize cooperativity among binding interactions to achieve high affinity and specificity. The significance of these observations is discussed within the context of possible mechanisms for the HLA-DM protein that regulates peptide presentation in vivo and the design of non-peptide molecules that can bind MHC II proteins and act as vaccines or immune modulators. © 2002 John Wiley & Sons, Inc. Med Res Rev, 22, No. 2, 168,203, 2002; DOI 10.1002/med.10006 [source] Grp94, the endoplasmic reticulum Hsp90, has a similar solution conformation to cytosolic Hsp90 in the absence of nucleotidePROTEIN SCIENCE, Issue 9 2009Kristin A. Krukenberg Abstract The molecular chaperone, Hsp90, is an essential eukaryotic protein that assists in the maturation and activation of client proteins. Hsp90 function depends upon the binding and hydrolysis of ATP, which causes large conformational rearrangements in the chaperone. Hsp90 is highly conserved from bacteria to eukaryotes, and similar nucleotide-dependent conformations have been demonstrated for the bacterial, yeast, and human proteins. There are, however, important species-specific differences in the ability of nucleotide to shift the conformation from one state to another. Although the role of nucleotide in conformation has been well studied for the cytosolic yeast and human proteins, the conformations found in the absence of nucleotide are less well understood. In contrast to cytosolic Hsp90, crystal structures of the endoplasmic reticulum homolog, Grp94, show the same conformation in the presence of both ADP and AMPPNP. This conformation differs from the yeast AMPPNP-bound crystal state, suggesting that Grp94 may have a different conformational cycle. In this study, we use small angle X-ray scattering and rigid body modeling to study the nucleotide free states of cytosolic yeast and human Hsp90s, as well as mouse Grp94. We show that all three proteins adopt an extended, chair-like conformation distinct from the extended conformation observed for the bacterial Hsp90. For Grp94, we also show that nucleotide causes a small shift toward the crystal state, although the extended state persists as the major population. These results provide the first evidence that Grp94 shares a conformational state with other Hsp90 homologs. [source] Granisetron, an antiemetic drug, and its cobalt complexACTA CRYSTALLOGRAPHICA SECTION C, Issue 2 2010Krishnan Ravikumar The crystal structures of granisetron [systematic name: 1-methyl- N -(9-methyl-9-azabicyclo[3.3.1]nonan-7-yl)indazole-3-carboxamide], C18H24N4O, (I), an antinauseant and antiemetic agent, and its CoII complex, diaqua[1-methyl- N -(9-methyl-9-azoniabicyclo[3.3.1]nonan-7-yl)indazole-3-carboxamide]cobalt(II) tetrachloride dodecahydrate, [Co(C18H25N4O)2(H2O)2]Cl4·12H2O, (II), have been determined by X-ray diffraction. The granisetron molecule is in an extended conformation in both structures. Twisting of the central carboxamide group facilitates the CoII coordination in (II). The CoII atom is located on an inversion centre. The azabicyclononane ring adopts a chair,boat conformation in both structures. The molecules in (I) are linked into centrosymmetric dimers and form tetracyclic rings through C,H...O hydrogen-bonding interactions. The simultaneous presence of free chloride ions in conjunction with a number of hydration water molecules in (II) provides interesting hydrogen-bond patterns. This study can aid in the investigation of the properties of metal complexes with active pharmaceuticals in which the drug molecules play the role of a ligand. [source] Dorzolamide hydrochloride: an antiglaucoma agentACTA CRYSTALLOGRAPHICA SECTION C, Issue 2 2007Balasubramanian Sridhar Dorzolamide hydrochloride [systematic name: (4S)- trans -4-ethylammonio-6-methyl-5,6-dihydro-4H -thieno[2,3- b]thiopyran-2-sulfonamide 7,7-dioxide chloride], C10H17N2O4S2+·Cl,, belongs to a class of drugs called carbonic anhydrase inhibitors. The ethylammonio side chain is in an extended conformation and is protonated at the N atom, which is hydrogen bonded to the Cl, anion. The dihedral angle between the planes of the thiophene ring and the sulfonamide group is 80.7,(1)°. A comparison is made with the dorzolamide bound in human carbonic anhydrase in the solid state. Hydrogen bonding is mediated by Cl, anions, resulting in indirect connectivity between the molecules. [source] Crystallographic report: 1,3-Bis[(trimethylsilylmethyl)dichlorostannyl]propane, [(Me3SiCH2)Cl2Sn]2(CH2)3APPLIED ORGANOMETALLIC CHEMISTRY, Issue 1 2003Dainis Dakternieks Abstract The dinuclear molecule of [(Me3SiCH2)Cl2Sn]2(CH2)3 adopts an extended conformation and features distorted tetrahedral tin centres, with the greatest distortion manifested in the CSnC angles of approximately 128,°. The distortions are ascribed to the influence of intermolecular Sn···Cl interactions. Copyright © 2002 John Wiley & Sons, Ltd. [source] Structural basis for the high-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinaseACTA CRYSTALLOGRAPHICA SECTION D, Issue 7 2008John S. Sack The crystal structure of unphosphorylated p38, MAP kinase complexed with a representative pyrrolotriazine-based inhibitor led to the elucidation of the high-affinity binding mode of this class of compounds at the ATP-binding site. The ligand binds in an extended conformation, with one end interacting with the adenine-pocket hinge region, including a hydrogen bond from the carboxyl O atom of Met109. The other end of the ligand interacts with the hydrophobic pocket of the binding site and with the backbone N atom of Asp168 in the DFG activation loop. Addition of an extended benzylmorpholine group forces the DFG loop to flip out of position and allows the ligand to make additional interactions with the protein. [source] Metal-free MIRAS phasing: structure of apo-S100A3ACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2002Peer R. E. Mittl S100 proteins are involved in metal-dependent intracellular signalling. Metal-free S100A3, a cysteine-rich Ca2+ - and Zn2+ -binding protein, has been crystallized by vapour diffusion under the strict exclusion of oxygen and in the absence of divalent metal ions. Metal binding induces large conformational changes, rendering the apo-S100A3 crystals very sensitive to various metal compounds. Therefore, the structure was solved by MIRAS phasing using potassium iodide and xenon derivatives. Iodide replaces a water molecule at the surface of the S100A3 protein, whereas xenon binds in a hydrophobic cavity at the dimer interface. Despite significant non-isomorphism, the combination of both derivatives was sufficient for structure determination. The overall apo-S100A3 structure resembles the structures of metal-free S100B and S100A6 solution structures. In contrast to the NMR structures, the EF-hand loops are well ordered in the apo-S100A3 crystal structure. In the N-terminal pseudo-EF-hand loop a water molecule occupies the position of the Ca2+ ion. The C-terminal canonical EF-hand loop shows an extended conformation and a different helix arrangement to other S100/metal complex crystal structures. [source] Conformations within soluble oligomers and insoluble aggregates revealed by resonance energy transferBIOPOLYMERS, Issue 4 2010Jyothi L. Digambaranath Abstract A fluorescently labeled 20-residue polyglutamic acid (polyE) peptide 20 amino acid length polyglutamic acid (E20) was used to study structural changes which occur in E20 as it co-aggregates with other unlabeled polyE peptides. Resonance energy transfer (RET) was performed using an o -aminobenzamide donor at the N-terminus and 3-nitrotyrosine acceptor at the C-terminus of E20. PolyE aggregates were not defined as amyloid, as they were nonfibrillar and did not bind congo red. Circular dichroism measurements indicate that polyE aggregation involves a transition from ,-helical monomers to aggregated ,-sheets. Soluble oligomers are also produced along with aggregates in the reaction, as determined through size exclusion chromatography. Time-resolved and steady-state RET measurements reveal four dominant E20 conformations: (1) a partially collapsed conformation (24 Å donor,acceptor distance) in monomers, (2) an extended conformation in soluble oligomers (>29 Å donor,acceptor distance), (3) a minor partially collapsed conformation (22 Å donor-acceptor distance) in aggregates, and (4) a major highly collapsed conformation (13 Å donor,acceptor distance) in aggregates. These findings demonstrate the use of RET as a means of determining angstrom-level structural details of soluble oligomer and aggregated states of proteins. © 2009 Wiley Periodicals, Inc. Biopolymers 93: 299,317, 2010. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] Conformational study on glycosylated asparagine-oligopeptides by NMR spectroscopy and molecular dynamics calculationsJOURNAL OF PEPTIDE SCIENCE, Issue 8 2005Stefania Mazzini Abstract The conformational properties of the homo oligomers of increasing chain length Boc-(Asn)n -NHMe (n = 2, 4, 5), (GlcNAc-,-Asn)n -NHMe (n = 2, 4, 5, 8) and Boc-[GlcNAc(Ac)3 -,-Asn]n -NHMe (n = 2, 4, 5) were studied by using NOE experiments and molecular dynamic calculations (MD). Sequential NOEs and medium range NOEs, including (i,i+2) interactions, were detected by ROESY experiments and quantified. The calculated inter-proton distances are longer than those characteristic of ,-turn secondary structures. Owing to the large conformational motions expected for linear peptides, MD simulations were performed without NMR constraints, with explicit water and by applying different treatments of the electrostatic interactions. In agreement with the NOE results, the simulations showed, for all peptides, the presence of both folded and unfolded structures. The existence of significant populations of ,-turn structures can be excluded for all the examined compounds, but two families of structures were more often recognized. The first one with sinusoidal or S-shaped forms, and another family of large turns together with some more extended conformations. Only the glycosylated pentapeptide shows in vacuo a large amount of structures with helical shaped form. The results achieved in water and in DMSO are compared and discussed, together with the effect of the glycosylation. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [source] Study of the conformational profile of the norbornane analogues of phenylalanineJOURNAL OF PEPTIDE SCIENCE, Issue 6 2002Arnau Cordomí Abstract The conformational profile of the eight stereoisomeric 2-amino-3-phenylnorbornane-2-carboxylic acids (2-amino-3-phenylbicyclo[2.2.1]heptane-2-carboxylic acids) has been assessed by computational methods. These molecules constitute a series of four enantiomeric pairs that can be considered as rigid analogues of either L - or D -phenylalanine. The conformational space of their N -acetyl methylamide derivatives has been explored within the molecular mechanics framework, using the parm94 set of parameters of the AMBER force field. Local minimum energy conformations have been further investigated at the ab initio level by means of the Hartree-Fock and second order Moller-Plesset perturbation energy calculations using a 6,31G(d) basis set. The results of the present work suggest that the bulky norbornane structure induces two kinds of conformational constraints on the residues. On one hand, those of a steric nature directly imposed by the bicycle on the peptide backbone and, on the other hand, those that limit the orientations attainable by the phenyl ring which, in turn, reduces further the flexibility of the peptide backbone. A comparative analysis of the conformational profile of the phenylnorbornane amino acids with that of the norbornane amino acids devoid of the ,-phenyl substituent suggests that the norbornane system hampers the residue to adopt extended conformations in favour of C7-like structures. However, the bicycle itself does not impart a clear preference for any of the two possible C7 minima. It is the aromatic side chain, which is forced to adopt an almost eclipsed orientation, that breaks this symmetry introducing a marked preference for a single region of the (,, ,) conformational space in each of the phenylalanine norbornane analogues investigated. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd. [source] Synthesis and characterization of thermally stable, high-modulus polyimides containing benzimidazole moietiesJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 8 2009Shuang Wang Abstract A series of novel benzimidazole-containing aromatic polyimides were prepared from synthesized 5,4,-diamino-2-phenyl benzimidazole (DAPBI), and commercial dianhydrides by the conventional two-step polymerization. The obtained films were amorphous and could afford flexible, transparent, and tough films with excellent thermal and mechanical properties. They showed high levels of tension strength of up to 234 MPa, modulus of up to 5.6 GPa without any stretching. According to thermal stability measurements, the glass-transition temperatures of the polymers were observed between 329 and 425 °C. The 5% weight-loss temperatures of most polyimides were above 600 °C in nitrogen. Excellent properties of these polyimides were proved to be attributed to the rigid-rod structure and hydrogen bond of intermacromolecular. SAXS and SEM results showed self-molecular orientation caused the formation of rod-like extended conformations. It was demonstrated that high degree of supramolecular order led to the increase of thermal stability and mechanical properties of the polyimide films. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2024,2031, 2009 [source] Native and nonnative conformational preferences in the urea-unfolded state of barstarPROTEIN SCIENCE, Issue 12 2004Neel S. Bhavesh NMR, nuclear magnetic resonance; HSQC, hetero-nuclear single-quantum coherence Abstract The refolding of barstar from its urea-unfolded state has been studied extensively using various spectroscopic probes and real-time NMR, which provide global and residue-specific information, respectively, about the folding process. Here, a preliminary structural characterization by NMR of barstar in 8 M urea has been carried out at pH 6.5 and 25°C. Complete backbone resonance assignments of the urea-unfolded protein were obtained using the recently developed three-dimensional NMR techniques of HNN and HN(C)N. The conformational propensities of the polypeptide backbone in the presence of 8 M urea have been estimated by examining deviations of secondary chemical shifts from random coil values. For some residues that belong to helices in native barstar, 13C, and 13CO secondary shifts show positive deviations in the urea-unfolded state, indicating that these residues have propensities toward helical conformations. These residues are, however, juxtaposed by residues that display negative deviations indicative of propensities toward extended conformations. Thus, segments that are helical in native barstar are unlikely to preferentially populate the helical conformation in the unfolded state. Similarly, residues belonging to ,-strands 1 and 2 of native barstar do not appear to show any conformational preferences in the unfolded state. On the other hand, residues belonging to the ,-strand 3 segment show weak nonnative helical conformational preferences in the unfolded state, indicating that this segment may possess a weak preference for populating a helical conformation in the unfolded state. [source] Electron capture dissociation mass spectrometry of peptide cations containing a lysine homologue: a mobile proton model for explaining the observation of b-type product ionsRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 21 2006Sunyoung Lee Eleven doubly protonated peptides with a residue homologous to lysine were investigated by electron capture dissociation mass spectrometry (ECD-MS). Lysine homologues provide the unique opportunity to examine the ECD fragmentation behavior by allowing us to vary the length of the lysine side chain, with minimal structural change. The lysine homologue has a primary amine side chain with a length that successively decreases by one methylene (CH2) unit from the CH2CH2CH2CH2NH2 of lysine and the accompanying decrease of its proton affinities: lysine (K), 1006.5(±7.2) kJ/mol; ornithine (K*), 1001.1(±6.6) kJ/mol; 2,4-diaminobutanoic acid (K**), 975.8(±7.4) kJ/mol; 2,3-diaminopropanoic acid (K***), 950.2(±7.2) kJ/mol. In general, the lysine-homologous peptides exhibited overall ECD fragmentation patterns similar to that of the lysine-containing peptides in terms of the locations, abundances, and ion types of products, such as yielding c+ and z+. ions as the dominant product ions. However, a close inspection of product ion mass spectra showed that ECD-MS for the alanine-rich peptides with an ornithinyl or 2,4-diaminobutanoyl residue gave rise to b ions, while the lysinyl-residue-containing peptides did not, in most cases, produce any b ions. The peptide selectivity in the generation of b+ ions could be understood from within the framework of the mobile proton model in ECD-MS, previously proposed by Cooper (Ref. 29). The exact mass analysis of the resultant b ions reveals that these b ions are not radical species but rather the cationic species with R-CO+ structure (or protonated oxozalone ion), that is, b+ ions. The absence of [M+2H]+. species in the ECD mass spectra and the selective b+ -ion formation are evidence that the peptides underwent H-atom loss upon electron capture, and then the resulting reduced species dissociated following typical MS/MS fragmentation pathways. This explanation was further supported by extensive b+ ions generated in the ECD of alanine-based peptides with extended conformations. Copyright © 2006 John Wiley & Sons, Ltd. [source] | ||||||||||