Welch W, Williams A J, Tinker A, Mitchell K E, Deslongchamps P, Lamothe J, Gerzon K, Bidasee K R, Besch H R, Airey J A, Sutko J L, Ruest L
Department of Biochemistry, University of Nevada, Reno 89557, USA.
Biochemistry. 1997 Mar 11;36(10):2939-50. doi: 10.1021/bi9623901.
Comparative molecular field analysis (CoMFA) was used to analyze the relationship between the structure of a group of ryanoids and the modulation of the calcium channel function of the ryanodine receptor. The conductance properties of ryanodine receptors purified from sheep heart were measured using the planar, lipid bilayer technique. The magnitude of the ryanoid-induced fractional conductance was strongly correlated to specific structural loci on the ligand. Briefly, electrostatic effects were more prominent than steric effects. The 10-position of the ryanoid had the greatest influence on fractional conductance. Different regions of the ligand have opposing effects on fractional conductance. For example, steric bulk at the 10-position is correlated with decreased fractional conductance, whereas steric bulk at the 2-position (isopropyl position) is correlated with increased fractional conductance. In contrast to fractional conductance, the 3-position (the pyrrole locus) had the greatest influence on ligand binding, whereas the 10-position had comparatively little influence on binding. Two possible models of ryanodine action, a direct (or channel plug) mechanism and an allosteric mechanism, were examined in light of the CoMFA. Taken together, the data do not appear to be consistent with direct interaction between ryanodine and the translocating ion. The data appear to be more consistent with an allosteric mechanism. It is suggested the ryanoids act by inducing or stabilizing a conformational change in the ryanodine receptor that results in the observed alterations in cation conductance.
采用比较分子场分析（CoMFA）来分析一组鱼尼丁类似物的结构与鱼尼丁受体钙通道功能调节之间的关系。使用平面脂质双层技术测量从羊心脏中纯化的鱼尼丁受体的电导特性。鱼尼丁诱导的分数电导幅度与配体上的特定结构位点密切相关。简而言之，静电效应比空间效应更显著。鱼尼丁类似物的10位对分数电导影响最大。配体的不同区域对分数电导有相反的影响。例如，10位的空间体积与分数电导降低相关，而2位（异丙基位置）的空间体积与分数电导增加相关。与分数电导相反，3位（吡咯位点）对配体结合影响最大，而10位对结合的影响相对较小。根据CoMFA研究了鱼尼丁作用的两种可能模型，即直接（或通道堵塞）机制和变构机制。总体而言，数据似乎与鱼尼丁和转运离子之间的直接相互作用不一致。数据似乎更符合变构机制。有人提出，鱼尼丁类似物通过诱导或稳定鱼尼丁受体的构象变化来发挥作用，从而导致观察到的阳离子电导改变。
