7xnn
From Proteopedia
human KCNQ1-CaM-ML277-PIP2 complex in state B
Structural highlights
DiseaseCALM3_HUMAN Romano-Ward syndrome;Catecholaminergic polymorphic ventricular tachycardia. The disease may be caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionCALM3_HUMAN Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding (PubMed:16760425, PubMed:31454269). Calcium-binding is required for the activation of calmodulin (PubMed:16760425, PubMed:31454269, PubMed:35568036). Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases, such as myosin light-chain kinases and calmodulin-dependent protein kinase type II (CaMK2), and phosphatases (PubMed:16760425, PubMed:35568036). Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425).[1] [2] [3] (Microbial infection) Required for C.violaceum CopC and S.flexneri OspC3 arginine ADP-riboxanase activity.[4] [5] [6] [7] Publication Abstract from PubMedThe 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 (PIP(2)) and a small-molecule ML277, we determined 2.5-3.5 A resolution cryo-electron microscopy structures of full-length human KCNQ1-calmodulin (CaM) complex in the apo closed, ML277-bound open, and ML277-PIP(2)-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(2) 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. Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.,Ma D, Zhong L, Yan Z, Yao J, Zhang Y, Ye F, Huang Y, Lai D, Yang W, Hou P, Guo J Proc Natl Acad Sci U S A. 2022 Nov 8;119(45):e2207067119. doi: , 10.1073/pnas.2207067119. Epub 2022 Nov 3. PMID:36763058[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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