Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.

ABSTRACT: The cardiac KCNQ1 potassium channel carries the important I_Ks 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 (PIP₂) 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-PIP₂-bound open states. ML277 binds at

SUBMITTER: Ma D 

PROVIDER: S-EPMC9661191 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature