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TitleStructural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 119, Issue 45, Page e2207067119, Year 2022
Publish dateNov 8, 2022
AuthorsDemin Ma / Ling Zhong / Zhenzhen Yan / Jing Yao / Yan Zhang / Fan Ye / Yuan Huang / Dongwu Lai / Wei Yang / Panpan Hou / Jiangtao Guo /
PubMed AbstractThe 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 ...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.
External linksProc Natl Acad Sci U S A / PubMed:36763058 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 3.5 Å
Structure data

33316

7xni

EMDB-33316, PDB-7xni:
human KCNQ1-CaM in apo state
Method: EM (single particle) / Resolution: 3.5 Å

33317

7xnk

EMDB-33317, PDB-7xnk:
human KCNQ1-CaM in complex with ML277
Method: EM (single particle) / Resolution: 2.6 Å

33318

7xnl

EMDB-33318, PDB-7xnl:
human KCNQ1-CaM-ML277-PIP2 complex in state A
Method: EM (single particle) / Resolution: 3.1 Å

33319

7xnn

EMDB-33319, PDB-7xnn:
human KCNQ1-CaM-ML277-PIP2 complex in state B
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-K:
Unknown entry

ChemComp-I0S:
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-1-sulfonyl)piperidine-2-carboxamide

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / potassium voltage-gated channel / ML277 / PIP2

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