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1.
Denis Kudryavtsev Anastasia Isaeva Daria Barkova Ekaterina Spirova Renata Mukhutdinova Igor Kasheverov Victor Tsetlin 《Molecules (Basel, Switzerland)》2021,26(5)
Slow-channel congenital myasthenic syndromes (SCCMSs) are rare genetic diseases caused by mutations in muscle nicotinic acetylcholine receptor (nAChR) subunits. Most of the known SCCMS-associated mutations localize at the transmembrane region near the ion pore. Only two SCCMS point mutations are at the extracellular domains near the acetylcholine binding site, α1(G153S) being one of them. In this work, a combination of molecular dynamics, targeted mutagenesis, fluorescent Ca2+ imaging and patch-clamp electrophysiology has been applied to G153S mutant muscle nAChR to investigate the role of hydrogen bonds formed by Ser 153 with C-loop residues near the acetylcholine-binding site. Introduction of L199T mutation to the C-loop in the vicinity of Ser 153 changed hydrogen bonds distribution, decreased acetylcholine potency (EC50 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca2+ rise (τ 14.2 ± 0.3 vs. 34.0 ± 0.4 s). These results shed light on molecular mechanisms of nAChR activation-desensitization and on the involvement of such mechanisms in channelopathy genesis. 相似文献
2.
We model the motion of a receptor on the membrane surface of a synapse as free Brownian motion in a planar domain with intermittent trappings in and escapes out of corrals with narrow openings. We compute the mean confinement time of the Brownian particle in the asymptotic limit of a narrow opening and calculate the probability to exit through a given small opening, when the boundary contains more than one. Using this approach, it is possible to describe the Brownian motion of a random particle in an environment containing domains with small openings by a coarse grained diffusion process. We use the results to estimate the confinement time as a function of the parameters and also the time it takes for a diffusing receptor to be anchored at its final destination on the postsynaptic membrane, after it is inserted in the membrane. This approach provides a framework for the theoretical study of receptor trafficking on membranes. This process underlies synaptic plasticity, which relates to learning and memory. In particular, it is believed that the memory state in the brain is stored primarily in the pattern of synaptic weight values, which are controlled by neuronal activity. At a molecular level, the synaptic weight is determined by the number and properties of protein channels (receptors) on the synapse. The synaptic receptors are trafficked in and out of synapses by a diffusion process. Following their synthesis in the endoplasmic reticulum, receptors are trafficked to their postsynaptic sites on dendrites and axons. In this model the receptors are first inserted into the extrasynaptic plasma membrane and then random walk in and out of corrals through narrow openings on their way to their final destination. 相似文献
3.
Blundell Tom L. Bolanos-Garcia Victor Chirgadze Dimitri Y. Harmer Nicholas J. Lo Thomas Pellegrini Luca Sibanda B. Lynn 《Structural chemistry》2002,13(3-4):405-412
Signaling in living systems needs to achieve high specificity, to be reversible, and to achieve high signal to noise. Signaling mediated by multiprotein systems has evolved that avoids the requirement for high-affinity binary complexes that would be difficult to reverse and which, in the overcrowded cell, would lead to excessive noise in the system. Symmetrical structures are only occasionally formed. When they are, it is principally to colocate components, for example, the tyrosyl kinases of growth factors, where dimers form. Symmetry is, however, often broken, presumably to create more sensitivity and specificity in the signaling system by assembling other components, into higher-order multiprotein systems. The binding of a single heparin to two 1:1 FGF:FGFR complexes is an example, as is the binding of a single ligase to the Xrcc4 dimer, perhaps so creating a further DNA-binding site. 相似文献
4.
Sungjae In Jongmin Kang 《Journal of inclusion phenomena and macrocyclic chemistry》2006,54(1-2):129-132
Methylene-bridged bis-imidazolium receptor 1 has been synthesized. Anion binding studies carried out using 1H NMR revealed that this compound displayed good affinities for acetate, while binding spherical halide anions weakly. 相似文献
5.
LIU Biao BAO Yong-li WEI Zhuang WU Yin MENG Xiang-ying LI Yu-xin YIN Wei-tian 《高等学校化学研究》2006,22(2):217-220
Introduction Activinisamemberofthetransforminggrowth factor(TGF)βsuperfamilyofextracellularsignaling proteins.Themembersofthisfamilyplayacriticalrole duringembryogenesisandinmaintainingtissuehomeo stasisinadultlife[1—3].DeregulatedTGFfamilysigna lingisi… 相似文献
6.
《Electroanalysis》2003,15(4):294-302
Macrocyclic lipophilic polyamines were applied as the sensory elements of polymeric liquid membrane electrodes. These hosts gain the anion receptor functionality upon protons uptake from the aqueous solutions. The electrodes studied were able to distinguish potentiometricaly isomers of monocharged and doublecharged forms of ethylene and benzene dicarboxylic acids. The selectivity of interaction between protonated hosts and anionic guests relays not only on the electrostatic interactions, but on hydrogen bounds formations as well. The influence of lipophilicity of protonated hosts on the potential response generation was discussed. 相似文献
7.
Tomomi Ikemoto Tatsuya Ito Atsuko Nishiguchi Kiminori Tomimatsu 《Tetrahedron》2004,60(48):10851-10857
The efficient synthesis of 2,3-dihydro-1-benzothiepine derivatives 4 has been developed. The intramolecular Claisen type reaction of the new products, 4-(o-formylphenylthio)butyrate 9, with alcoholate in dialkylcarbonate as a solvent afforded 4 in good yields. According to this new procedure, we have accomplished the practical preparation of CCR5 antagonist 1 as a candidate for oral HIV-1 therapy. 相似文献
8.
W 7-agarose是常用的细胞外CaM功能的拮抗剂,本实验采用荧光光谱法研究了水溶液中钙调素拮抗剂W 7-agarose与植物胞外钙调素的相互结合反应。W 7-agarose是一种将W 7-共价连接到颗粒型agarose(琼脂糖)的粒子。W 7-agarose颗粒较大且容易沉淀,静置5m in后,溶液中的荧光强度完全由游离的CaM产生。在溶液中加入W 7-agarose后,溶液中一部分CaM与其结合后沉降至荧光比色皿底部,导致溶液中CaM的荧光强度下降。由此可以确定溶液中游离CaM的浓度。根据公式lg{[Q]t(F0-F)/F0}=nlg{[Q]tF/F0} lgnK[B]t,从而计算出配位体系的结合常数和配比。研究表明:二者以摩尔比1∶1结合,其平衡常数为4.9×105。由此进一步计算了W 7-agarose对胞外钙调素的拮抗率,在拮抗剂W 7-agarose浓度达到15~20μmol/L时,拮抗率可达到90%以上,与文献报道的生物学体内实验结果一致,从分子水平上解释了W 7-agarose与CaM的结合作用。 相似文献
9.
Marta Filizola Maria Carteni-Farina Juan J. Perez 《Journal of computer-aided molecular design》1999,13(4):397-407
3D models of the opioid receptors , and were constructed using BUNDLE, an in-house program to build de novo models of G-protein coupled receptors at the atomic level. Once the three opioid receptors were constructed and before any energy refinement, models were assessed for their compatibility with the results available from point-site mutations carried out on these receptors. In a subsequent step, three selective antagonists to each of three receptors (naltrindole, naltrexone and nor-binaltorphamine) were docked onto each of the three receptors and subsequently energy minimized. The nine resulting complexes were checked for their ability to explain known results of structure-activity studies. Once the models were validated, analysis of the distances between different residues of the receptors and the ligands were computed. This analysis permitted us to identify key residues tentatively involved in direct interaction with the ligand. 相似文献
10.
Chiral α,ω-diesters react under high-pressure conditions (10 kbar) with α,ω-diamines to give chiral cyclic tetraamides of C2-symmetry. The complexation properties of tetraamides towards alkali metal cations (Li+, Na+, K+, Rb+ and Cs+) were estimated on the basis of ESI-MS spectra. 相似文献