National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.
Nat Commun. 2022 Apr 19;13(1):2084. doi: 10.1038/s41467-022-29728-0.
The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type Ca3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. Ca3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type Ca channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the Ca3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.
低电压激活的 T 型钙通道调节细胞兴奋性和静息膜电位的振荡行为，触发许多生理事件，并与许多疾病有关。在这里，我们确定了人源 T 型 Ca3.3 通道在缺乏和存在抗高血压药物米贝地尔、抗痉挛药物奥替溴铵和抗精神病药物匹莫齐特时的结构。Ca3.3 包含来自 III 结构域的长弯曲 S6 螺旋，带有正电荷区域突出到细胞质中，这对于低电压下 T 型钙通道的激活至关重要。结合药物的结构清楚地说明了这些结构不同的化合物如何结合到 Ca3.3 通道的同一中央腔中，但药物与其周围残基之间的相互作用明显不同。磷脂分子以不同的程度渗透到中央腔中，形成结合口袋，并在稳定抑制剂方面发挥重要作用。这些结构阐明了通道门控、药物识别和作用的机制，从而为开发针对相关疾病的有效和亚型特异性药物治疗指明了方向。
