Department of Biophysics, and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, 999078, China.
Proc Natl Acad Sci U S A. 2022 Nov 8;119(45):e2207067119. doi: 10.1073/pnas.2207067119. Epub 2022 Nov 3.
The cardiac KCNQ1 potassium channel carries the important current and controls the heart rhythm. Hundreds of mutations in KCNQ1 can cause life-threatening cardiac arrhythmia. Although KCNQ1 structures have been recently resolved, the structural basis for the dynamic electro-mechanical coupling, also known as the voltage sensor domain-pore domain (VSD-PD) coupling, remains largely unknown. In this study, utilizing two VSD-PD coupling enhancers, namely, the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP) and a small-molecule ML277, we determined 2.5-3.5 Å resolution cryo-electron microscopy structures of full-length human KCNQ1-calmodulin (CaM) complex in the apo closed, ML277-bound open, and ML277-PIP-bound open states. ML277 binds at the "elbow" pocket above the S4-S5 linker and directly induces an upward movement of the S4-S5 linker and the opening of the activation gate without affecting the C-terminal domain (CTD) of KCNQ1. PIP binds at the cleft between the VSD and the PD and brings a large structural rearrangement of the CTD together with the CaM to activate the PD. These findings not only elucidate the structural basis for the dynamic VSD-PD coupling process during KCNQ1 gating but also pave the way to develop new therapeutics for anti-arrhythmia.
心脏 KCNQ1 钾通道携带重要电流并控制心脏节律。KCNQ1 中的数百种突变可导致危及生命的心律失常。尽管最近已经解析了 KCNQ1 的结构，但动态机电耦合（也称为电压传感器域-孔域（VSD-PD）耦合）的结构基础在很大程度上仍然未知。在这项研究中，我们利用两种 VSD-PD 耦合增强剂，即膜脂质磷脂酰肌醇 4,5-二磷酸（PIP）和小分子 ML277，确定了全长人 KCNQ1-钙调蛋白（CaM）复合物在apo 关闭、ML277 结合打开和 ML277-PIP 结合打开状态下的 2.5-3.5Å分辨率冷冻电镜结构。ML277 结合在 S4-S5 连接子上方的“肘”口袋中，并直接诱导 S4-S5 连接子向上移动和激活门打开，而不影响 KCNQ1 的 C 端结构域（CTD）。PIP 结合在 VSD 和 PD 之间的裂隙处，并与 CaM 一起引起 CTD 的大规模结构重排，从而激活 PD。这些发现不仅阐明了 KCNQ1 门控过程中动态 VSD-PD 耦合的结构基础，也为开发抗心律失常的新疗法铺平了道路。
