Welch W, Sutko J L, Mitchell K E, Airey J, Ruest L
Department of Biochemistry, University of Nevada, Reno 89557, USA.
Biochemistry. 1996 Jun 4;35(22):7165-73. doi: 10.1021/bi9527294.
Ryanodine, a natural product, is a complex modulator of a class of intracellular Ca2+ release channels commonly called the ryanodine receptors. Ryanodine analogs can cause the channel to persist in long-lived, subconductance states or, at high ligand concentrations, in closed, nonconducting states. In this paper, we further explore the relationship between structure and ryanodine binding to striated muscle. Ryanodine, 3-epiryanodine, and 10-ryanodine are three structural isomers of ryanodine. The dissociation constants of these compounds were measured using rabbit skeletal muscle ryanodine receptors. Placing the pyrrole carbonyl group at the 3-epi- and 10-positions of ryanodol largely restores the large loss of binding energy observed when ryanodine is hydrolyzed to ryanodol. Comparative molecular field analysis successfully predicts the enhanced binding and indicates that the pyrrole group controls the orientation of ligand binding. We propose that the ryanoids are reorientated in the binding site of the ryanodine receptors such that the pyrrole always occupies the same subsite. By applying this model, the binding constants of other ryanoids are predicted.
莱克多巴胺是一种天然产物，是一类通常被称为莱克多巴胺受体的细胞内钙离子释放通道的复杂调节剂。莱克多巴胺类似物可使通道持续处于长寿命的亚电导状态，或者在高配体浓度下处于关闭的非传导状态。在本文中，我们进一步探讨了结构与莱克多巴胺与横纹肌结合之间的关系。莱克多巴胺、3-表莱克多巴胺和10-莱克多巴胺是莱克多巴胺的三种结构异构体。使用兔骨骼肌莱克多巴胺受体测量了这些化合物的解离常数。将吡咯羰基置于莱克多醇的3-表位和10-位，在很大程度上恢复了莱克多巴胺水解为莱克多醇时观察到的结合能的大幅损失。比较分子场分析成功地预测了增强的结合，并表明吡咯基团控制配体结合的方向。我们提出，莱克多巴胺类化合物在莱克多巴胺受体的结合位点重新定向，使得吡咯总是占据相同的亚位点。通过应用该模型，预测了其他莱克多巴胺类化合物的结合常数。
