7XNI

human KCNQ1-CaM in apo state

7XNI の概要

• エントリーDOI: 10.2210/pdb7xni/pdb
• EMDBエントリー: 33316
• 分子名称: Potassium voltage-gated channel subfamily KQT member 1, Calmodulin-3 (2 entities in total)
• 機能のキーワード: potassium voltage-gated channel, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 384410.97

構造登録者

Ma, D.,Guo, J. (登録日: 2022-04-28, 公開日: 2022-12-14, 最終更新日: 2024-07-03)

主引用文献

Ma, D.,Zhong, L.,Yan, Z.,Yao, J.,Zhang, Y.,Ye, F.,Huang, Y.,Lai, D.,Yang, W.,Hou, P.,Guo, J.
Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.
Proc.Natl.Acad.Sci.USA, 119:e2207067119-e2207067119, 2022

PubMed Abstract: 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.

PubMed: 36763058
DOI: 10.1073/pnas.2207067119

実験手法

ELECTRON MICROSCOPY (3.5 Å)