Home About us Contact
|
Home About us Contact | ||
|
|
||
Other Ligands (other + ligand)
Selected AbstractsCharacterization of conantokin Rl -A: molecular phylogeny as structure/function studyJOURNAL OF PEPTIDE SCIENCE, Issue 8 2010Konkallu H. Gowd Abstract A multidisciplinary strategy for discovery of new Conus venom peptides combines molecular genetics and phylogenetics with peptide chemistry and neuropharmacology. Here we describe application of this approach to the conantokin family of conopeptides targeting NMDA receptors. A new conantokin from Conus rolani, ConRl -A, was identified using molecular phylogeny and subsequently synthesized and functionally characterized. ConRl -A is a 24-residue peptide containing three ,-carboxyglutamic acid residues with a number of unique sequence features compared to conantokins previously characterized. The HPLC elution of ConRl -A suggested that this peptide exists as two distinct, slowly exchanging conformers. ConRl -A is predominantly helical (estimated helicity of 50%), both in the presence and absence of Ca++. The order of potency for blocking the four NMDA receptor subtypes by ConRl -A was NR2B > NR2D > NR2A > NR2C. This peptide has a greater discrimination between NR2B and NR2C than any other ligand reported so far. In summary, ConRl -A is a new member of the conantokin family that expands our understanding of structure/function of this group of peptidic ligands targeted to NMDA receptors. Thus, incorporating phylogeny in the discovery of novel ligands for the given family of ion channels or receptors is an efficient means of exploring the megadiverse group of peptides from the genus Conus. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd. [source] Genetic variation of the human glycine receptor subunit genes GLRA3 and GLRB and susceptibility to idiopathic generalized epilepsiesAMERICAN JOURNAL OF MEDICAL GENETICS, Issue 6 2001Diana Sobetzko Abstract Alterations of glycine receptor ,1 and , subunit genes have been associated with hypertonic motor disorders in both mice and humans. Mutations in genes encoding other ligand- and voltage-gated ion channels have been identified in rare monogenic forms of idiopathic generalized epilepsies (IGE). We tested the hypothesis that allelic variants of the glycine receptor subunit genes, GLRA3 and GLRB, both localized on chromosome 4q, confer susceptibility to common subtypes of IGE. Mutation screening was carried out in index patients of 14 IGE families. No pathogenic mutation was found, but two intronic polymorphisms were detected in the GLRB gene, and four intronic, three exonic, and one 3,-UTR polymorphisms were identified for the GLRA3 gene. Subsequent screening for exonic and 3,-UTR polymorphisms in GLRA3 showed no statistical difference between a group of sporadic IGE patients (n,=,104) and a control group (n,=,141). The genotype frequencies for exonic and 3,-UTR polymorphisms in GLRA3 showed no statistically significant difference between IGE patients (n,=,104) and an ethnically matched control group (n,=,141). Thus, no association between IGE and alterations in GLRA3 or GLRB genes could be detected, indicating that both genes do not play a major causative role in the epileptogenesis of common IGE subtypes. Still, these novel single nucleotide polymorphisms may be useful markers for candidate gene analyses of other disorders. © 2001 Wiley-Liss, Inc. [source] Changes in protein conformation and dynamics upon complex formation of brain-derived neurotrophic factor and its receptor: Investigation by isotope-edited Fourier transform IR spectroscopyBIOPOLYMERS, Issue 1 2002Tiansheng Li Abstract The interactions of brain-derived neurotrophic factor (BDNF) with the extracellular domain of its receptor (trkB) are investigated by employing isotope-edited Fourier transform IR (FTIR) spectroscopy. The protein secondary structures of individual BDNF and trkB in solutions are compared with those in their complex. The temperature dependence of the secondary structures of BDNF, trkB, and their complex is also investigated. Consistent with the crystal structure, we observe by FTIR spectroscopy that BDNF in solution contains predominantly , strands (,53%) and relatively low contents of other secondary structures including , turns (,16%), disordered structures (,12%), and loops (,18%) and is deficient in , helix. We also observe that trkB in solution contains mostly , strands (52%) and little , helix. Conformational changes in both BDNF and trkB are observed upon complex formation. Specifically, upon binding of BDNF, the conformational changes in trkB appear to involve mostly , turns and disordered structures while the majority of the ,-strand conformation remains unchanged. The IR data indicate that some of the disordered structures in the loop regions are likely converted to , strands upon complex formation. The FTIR spectral data of BDNF, trkB, and their complex indicate that more amide NH groups of trkB undergo H,D exchange within the complex than those of the ligand-free receptor and that the thermal stability of trkB is decreased slightly upon binding of BDNF. The FT-Raman spectra of BDNF, trkB, and their complex show that the six intramolecular disulfide bonds of trkB undergo significant conformational changes upon binding of BDNF as a result of changes in the tertiary structure of trkB. Taken together, the FTIR and Raman data are consistent with the loosening of the tertiary structure of trkB upon binding of BDNF, which leads to more solvent exposure of the amide NH group and decreased thermal stability of trkB. This finding reveals an intriguing structural property of the neurotrophin ligand,receptor complex that is in contrast to other ligand,receptor complexes such as a cytokine,receptor complex that usually shows protection of the amide NH group and increased thermal stability upon complex formation. © 2002 John Wiley & Sons, Inc. Biopolymers (Biospectroscopy) 67: 10,19, 2002; DOI 10.1002/bip.10038 [source] Novel estrogen receptor ligands and their structure,activity relationship evaluated by scintillation proximity assay for high-throughput screeningDRUG DEVELOPMENT RESEARCH, Issue 4 2005Ling He Abstract The estrogen receptor (ER) is an important drug target with allosteric characteristics that binds orthotopic hormones and other ligands. A recently developed scintillation proximity (SPA)-based assay for high-throughput screening (HTS) of compound libraries was used to identify novel estrogen receptor ligands that might have ER subtype selective binding activity. Radioligand binding was determined in a multi-detector scintillation counter designed for microtitration plates. Equilibrium binding experiments and kinetic competition tests were performed with [3H]-estradiol and human ER, and ER, receptors. A library of 6,000 structurally diverse compounds was screened. From this, several novel ligands were identified that showed pronounced subtype-selective differences in ligand binding for ER, and ER,. The observed equilibrium dissociation constant (Kd) for the binding of [3H]estradiol to ER, and ER, receptors were approximately 0.25 and 0.64 nM, respectively. When 17,-estradiol, raloxifene and daidzein were tested for binding affinity to ER, in a competition assay, the IC50 values were 0.34, 1.31, and 75.6 nM, respectively. When tested for binding affinity to ER,, the IC50 values were 1.05, 11.4, and 10.6 nM, respectively. The results obtained show that the methodology is valid in comparison to previously published data regarding estradiol and other standard compounds (raloxifene and daidzein) binding characteristics of estrogen receptors. The assay is also well suited to applied research as a tool in HTS of compound libraries in the search of ER ligands. Several novel active compounds were identified and selected as potent ER subtype ligands. Drug Dev Res 64:203,212, 2005. © 2005 Wiley-Liss, Inc. [source] Mobilization of metals from uranium mine waste: the role of pyoverdines produced by Pseudomonas fluorescensGEOBIOLOGY, Issue 4 2010F. EDBERG Microorganisms produce chelating agents, such as siderophores and other ligands, which allow them to mobilize and scavenge essential elements from the environment when bioavailability is low. To better understand the effects of biologically mediated leaching of metals from mine waste, Pseudomonas fluorescens was cultivated in the presence of processed ore from the former uranium mine in Ranstad, southern Sweden. Light conditions, the concentration of the mineral source and oxygen availability were varied. The presence of ore in the culture flasks enhanced bacterial growth and raised the pH of the culture medium. Increasing the amount of ore or enhancing aeration of the medium further encouraged cell growth and pH rise. Bacteria mobilized Fe, Ni and Co from the ore. Fe-siderophore complexes were detected and estimated to be present at approximately 9 ,m. In the presence of bacteria and light, dissolved Fe and U concentrations were higher compared to dark conditions. Increasing the amount of ore resulted in higher dissolved Ni concentrations but lower dissolved Fe, most likely due to precipitate formation. Data from this study support siderophore production by bacteria that allowed mobilization of essential nutrients from the processed ore. However, the availability of potentially toxic metals like Ni and U may also be enhanced. Microbial-promoted mobilization could contribute to leaching of toxic metals in current and historic mining areas. This process should be considered during design and implementation of remediation projects where trace metals are of environmental concern. [source] A Density Functional Study of Ethylene Insertion into the M-methyl (M = Ti, Zr) Bond for Different Catalysts, with a QM/MM Model for the Counterion, B(C6F5)3CH3,ISRAEL JOURNAL OF CHEMISTRY, Issue 4 2002Kumar Vanka Single site homogeneous catalysts have been studied extensively in recent years as alternatives to traditional heterogeneous catalysts. The current theoretical study uses density functional theory to study the insertion process of the ethylene monomer into the titanium-carbon chain for contact ion-pair systems of the type [L1L2TiCH3 -,-CH3 -B(C6F5)3], where L1, L2, are Cp, NPH3, and other ligands. Different modes of approach cis and trans to the ,-CH3 bridge were considered. The counterion, B(C6F5)3CH3,, was modeled by QM/MM methods. The value of ,Htot,the total barrier to insertion,was found to be positive (in the range of 4,15 kcal/mol). The ability of the ancillary ligands, L1 and L2, to stabilize the ion-pair was found to be an important factor in determining the value of ,Htot. On replacing the titanium metal center with zirconium, the ,Htot values were found to be lowered (in the range of 2,9 kcal/mol), indicating that they would be better catalysts than their titanium analogues. The size of the ligands L1 and L2 was increased by replacing hydrogens in the ligands with tertiary butyl groups. The value of ,Htot was found to increase (in the range of 10,28 kcal/mol) in contrast to the simple systems, for both the cis and trans cases of approach, with the cis mode of approach giving lower values of ,Htot. Solvent effects were incorporated with cyclohexane (, = 2.023) as the solvent, and were found to have a minor influence, ±(0.5,1.5) kcal/mol) on the insertion barrier for all the cases studied. [source] Vibrational spectra of bis(L -ornithinium) chloride nitrate sulfateJOURNAL OF RAMAN SPECTROSCOPY, Issue 1 2005S. Ramaswamy Abstract The Raman and infrared absorption spectra of 2(C5H14N2O22+)·Cl,·NO3,·SO42, crystal containing three anions were recorded at room temperature and were interpreted in the light of crystal structure data. The presence of a carbonyl group was identified. The carboxylic group was found to exist as COOH. The formation of OH···O, NH···O and NH···Cl asymmetric hydrogen bonds contributes considerably to the crystal cohesion and is responsible for the changes in the position and intensity of several bands. The vibrational spectra show that the anions were found to coordinate through hydrogen bonding interactions to other ligands in the crystal. The lattice wavenumbers of the halide radical (chlorine anion) were also assigned in terms of hydrogen bond vibrations. Copyright © 2004 John Wiley & Sons, Ltd. [source] Raman and IR spectral studies of D -phenylglycinium perchlorateJOURNAL OF RAMAN SPECTROSCOPY, Issue 9 2002S. Ramaswamy The Raman and infrared spectra of D -phenylglycinium perchlorate were recorded at room temperature. Tentative vibrational assignments of the observed wavenumbers were made by comparison with the vibrational wavenumbers of glycine, phenylalanine and other similar compounds. Anions were found to coordinate through hydrogen bonding interactions to other ligands in the crystal, affecting the Td symmetry and thereby causing the degeneracies of several modes to be removed. The extensive intermolecular hydrogen bonding in the crystal leads to a shift of bands due to the stretching and bending modes of various functional groups. The broadening and appearance of multiple bands for the carbonyl stretching mode due to the resonance interaction is also discussed. Copyright © 2002 John Wiley & Sons, Ltd. [source] The kinetics of competitive antagonism of nicotinic acetylcholine receptors at physiological temperatureTHE JOURNAL OF PHYSIOLOGY, Issue 4 2008Deeptankar Demazumder Detailed information about the ligand-binding site of nicotinic acetylcholine receptors has emerged from structural and mutagenesis experiments. However, these approaches provide only static images of ligand,receptor interactions. Kinetic measurements of changes in protein function are needed to develop a more dynamic picture. Previously, we measured association and dissociation rate constants for competitive inhibition of current through embryonic muscle acetylcholine receptor channels at 25°C. Little is known about competitive antagonism at physiological temperatures. Here, we performed measurements at 37°C and used thermodynamics to estimate the energetics of antagonism. We used rapid solution exchange protocols to determine equilibrium and kinetics of inhibition of acetylcholine-activated currents in outside-out patches by (+)-tubocurarine, pancuronium and cisatracurium. Kinetic rates as high as 600 s,1 were resolved by this technique. Binding was primarily enthalpy driven. The 12°C increase in temperature decreased equilibrium antagonist binding by 1.7- to 1.9-fold. In contrast, association and dissociation rate constants increased 1.9- to 6.0-fold. Activation energies for dissociation were 90 ± 6, 106 ± 8 and 116 ± 10 kJ mol,1 for cisatracurium, (+)-tubocurarine and pancuronium, respectively. The corresponding apparent activation energies for association were 38 ± 6, 85 ± 6 and 107 ± 13 kJ mol,1. The higher activation energy for association of (+)-tubocurarine and pancuronium compared with cisatracurium is notable. This may arise from either a more superficial binding site for the large antagonist cisatracurium compared to the other ligands, or from a change in receptor conformation upon binding of (+)-tubocurarine and pancuronium but not cisatracurium. Differences in ligand desolvation and ligand conformation are not likely to be important. [source] Poly[bis(,-4-benzoyl-1-isonicotinoylthiosemicarbazide-,2N:S)dichloridocadmium(II)]ACTA CRYSTALLOGRAPHICA SECTION C, Issue 5 2010Yu-Bo Wang The asymmetric unit of the title complex, [CdCl2(C14H12N4O2S)2]n, consists of one CdII ion located on the crystallographic inversion centre, one 4-benzoyl-1-isonicotinoylthiosemicarbazide ligand and one chloride ligand. The central CdII ion adopts a distorted octahedral coordination geometry formed by two pyridyl N atoms of two ligands, two S atoms of two other ligands and two chloride ligands. The thiosemicarbazide ligands act as bridges, linking the metal ions into a two-dimensional layered structure parallel to the bc plane. Intermolecular N,H...O hydrogen bonds and C,H..., interactions exist between adjacent layers. [source] Two- and three-dimensional hydrated coordination polymers of diaqualanthanum(3+) ions with 2-hydroxypropanedioate, oxalate and acetate anions as bridging ligandsACTA CRYSTALLOGRAPHICA SECTION C, Issue 4 2009Rajesh Koner The title compounds, poly[[tetraaquadi-,-2-hydroxypropanedioato-,-oxalato-dilanthanum(III)] tetrahydrate], {[La2(C2O4)(C3H2O5)2(H2O)4]·4H2O}n, (I), and poly[[tetra-,-acetato-tetraaqua-,-oxalato-dilanthanum(III)] dihydrate], {[La2(C2O4)(C2H3O2)4(H2O)4]·2H2O}n, (II), represent crystalline hydrates of coordination polymers of diaqualanthanum(3+) ions with different combinations of bridging carboxylate ligands, viz. 2-hydroxypropanedioate and oxalate in a 2:2:1 ratio in (I), and acetate and oxalate in a 2:4:1 ratio in (II). While the acetate component was one of the reactants used, the other ligands were obtained in situ by aerial oxidation of the dihydroxyfumaric acid present in the reactions. The crystal structure of (I) consists of two-dimensional polymeric arrays with water molecules intercalated between and hydrogen bonded to the arrays. The oxalate components are located on inversion centres. The crystal structure of (II) reveals an open three-dimensional polymeric connectivity between the interacting components, with the solvent water molecules incorporated within the intralattice voids and hydrogen bonded to the polymeric framework. The LaIII ion and the noncoordinated water molecules are located on axes of twofold symmetry. The oxalate group is centred at the 222 symmetry site, the intersection of the three rotation axes. The coordination number of the LaIII ion in the two structures is 10. The significance of this study lies mainly in the characterization of two new coordination polymers, as well as in the confirmation that dihydroxyfumaric acid tends to rearrange to form smaller components in standard laboratory procedures, and should be considered a poor reagent for formulating hybrid coordination polymers with metal ions. [source] Crystallization to obtain protein,ligand complexes for structure-aided drug designACTA CRYSTALLOGRAPHICA SECTION D, Issue 6 2006Dennis E. Danley The use of X-ray crystallography to derive three-dimensional structures for structure-aided drug design (SADD) is a common activity in drug discovery today. In this process, the structures of inhibitors or other ligands of interest complexed with their macromolecular target are solved and the structural information is used iteratively to design new molecules. The ability to form cocrystal complexes between a target protein and a ligand is essential to this process and therefore is of considerable interest to anyone practicing in this field. In the course of obtaining the necessary ligand,protein crystals, even with crystallization conditions well established for a protein of interest, obtaining co-structures with inhibitors either through cocrystallization or soaking is too often not successful. There are numerous potential reasons for this lack of success and this article outlines a number of possible factors that may be involved and discusses considerations that should be taken into account when designing successful experiments to obtain iterative costructures. [source] Medicinal Organometallic Chemistry: Designing Metal Arene Complexes as Anticancer AgentsCHEMISTRY - AN ASIAN JOURNAL, Issue 11 2008Abstract The field of medicinal inorganic chemistry is rapidly advancing. In particular organometallic complexes have much potential as therapeutic and diagnostic agents. The carbon-bound and other ligands allow the thermodynamic and kinetic reactivity of the metal ion to be controlled and also provide a scaffold for functionalization. The establishment of structure,activity relationships and elucidation of the speciation of complexes under conditions relevant to drug testing and formulation are crucial for the further development of promising medicinal applications of organometallic complexes. Specific examples involving the design of ruthenium and osmium arene complexes as anticancer agents are discussed. [source] | |||||||||||||||||||||||||