Structural Basis of the Modulation of the Voltage‐Gated Calcium Ion Channel Cav1.1 by Dihydropyridine Compounds**,Angewandte Chemie International Edition

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Structural Basis of the Modulation of the Voltage‐Gated Calcium Ion Channel Cav1.1 by Dihydropyridine Compounds**
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2020-10-30 , DOI: 10.1002/anie.202011793
Shuai Gao ₁ , Nieng Yan ₁

Affiliation

1,4‐Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L‐type voltage‐gated Ca²⁺ (Ca_v) channels. DHP compounds exhibit chirality‐specific antagonistic or agonistic effects. The structure of rabbit Ca_v1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remained elusive. Herein, we report five cryo‐EM structures of nanodisc‐embedded Ca_v1.1 in the presence of the bestselling drug amlodipine, a DHP antagonist (R)‐(+)‐Bay K8644, and a titration of its agonistic enantiomer (S)‐(−)‐Bay K8644 at resolutions of 2.9–3.4 Å. The amlodipine‐bound structure reveals the molecular basis for the high efficacy of the drug. All structures with the addition of the Bay K8644 enantiomers exhibit similar inactivated conformations, suggesting that (S)‐(−)‐Bay K8644, when acting as an agonist, is insufficient to lock the activated state of the channel for a prolonged duration.

中文翻译：

二氢吡啶化合物调节电压门控钙离子通道 Cav1.1 的结构基础**

1,4-二氢吡啶 (DHP) 是最常用的抗高血压药，通过抑制 L 型电压门控 Ca ²⁺ (Ca _v ) 通道发挥作用。 DHP 化合物表现出手性特异性拮抗或激动作用。与非手性药物硝苯地平结合的兔 Ca _v 1.1 的结构揭示了 DHP 药物的一般结合模式，但手性特异性的分子基础仍然难以捉摸。在此，我们报告了在畅销药物氨氯地平、DHP 拮抗剂 ( R )-(+)-Bay K8644 存在下纳米圆盘嵌入 Ca _v 1.1 的五种冷冻电镜结构，以及其激动性对映体 ( S )- 的滴定(−)-Bay K8644，分辨率为 2.9–3.4 Å。氨氯地平结合结构揭示了该药物高效的分子基础。添加Bay K8644对映体的所有结构都表现出类似的失活构象，表明( S )-(−)-Bay K8644作为激动剂时，不足以长时间锁定通道的激活状态。

更新日期：2020-10-30

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