Structural determinants of high-affinity binding of ryanoids to the vertebrate skeletal muscle ryanodine receptor: a comparative molecular field analysis.
Structural determinants of high-affinity binding of ryanoids to the vertebrate skeletal muscle ryanodine receptor: a comparative molecular field analysis.
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ryanoids 与脊椎动物骨骼肌 ryanodine 受体高亲和力结合的结构决定因素：比较分子场分析。
DOI：
10.1021/bi00186a006
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发表时间：
1994
期刊：
影响因子：
2.9
通讯作者：
Sutko,JL
中科院分区：
文献类型：
--
作者：
Welch,W;Ahmad,S;Airey,JA;Gerzon,K;Humerickhouse,RA;BeschJr,HR;Ruest,L;Deslongchamps,P;Sutko,JL
1994年2月21日接收的修订版Mandarin pt®摘要：Ryanodine与特异性膜蛋白结合，改变细胞内膜的钙渗透性。在这项研究中，19 ryanoids被分离或合成和结构相关的结合到脊椎动物骨骼肌ryanodine受体的强度。全局极小值的确定是通过分子力学和动力学的应用，并通过构象空间的系统搜索得到的。总的来说，空间和静电的因素同样有助于实验确定的解离常数的差异。占主导地位的静电相互作用定位于分子非极性区域中的羟基。吡咯和异丙基基团一起位于分子的一极，对配体和受体之间的空间相互作用具有最大的影响。我们认为ryanodine与吡咯和异丙基基团深埋在蛋白质裂缝内的受体结合。这种排列对吡咯和异丙基的构象特别重要。相反，相反的一极似乎位于结合口袋的入口处，因为放置在兰尼定9位的大体积加合物对结合的影响最小。例如，合成了一种荧光ryanodine加合物，其解离常数接近ryanodine的解离常数。详细的研究揭示了ryanoid和受体之间的微妙相互作用。在许多情况下，改变结合强度的主要因素被发现是远离共价修饰位点的分子的构象改变。
Revised Manuscript Received February 21, 1994® abstract: Ryanodine binds to specificmembrane proteins, altering the calcium permeabilityof intracellular membranes. In this study 19 ryanoids were isolated or synthesized and the structures correlated to the strength of binding to vertebrate skeletal muscle ryanodine receptors. Global minima were determined by employment of molecular mechanics and dynamics augmented by systematic searching of conformational space. Overall, steric and electrostatic factors contribute about equally to the differences in the experimentally determined dissociation constants. The dominant electrostatic interaction is localized to a hydroxyl group in an apolar region of the molecule. The pyrrole and isopropyl groups located together at one pole of the molecule have the greatest effect on steric interactions between ligand and receptor. We suggest ryanodine binds to the receptor with the pyrrole and isopropyl groups buried deep inside a cleft inthe protein. This arrangement places special importance on the conformation of the pyrrole and isopropyl groups. In contrast, the opposite pole appears to be positioned at the entrance of the binding pocket because bulky adducts placed in the 9 position of ryanodine alter binding minimally. For example, a fluorescent ryanodine adduct was synthesized which has a dissociation constant close to that of ryanodine. Detailed examination reveals subtle interactions between ryanoid and receptor. In many cases, the major factors altering the strength of binding were found to be conformational alterations in the moleculeremote from the site of covalent modification.