Vascular KATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides

Min Woo Sung, Zhongying Yang, Camden M. Driggers, Bruce L. Patton, Barmak Mostofian, John D. Russo, Daniel M. Zuckerman, Show Ling Shyng

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cant_u syndrome. Unique among KATP isoforms, they lack spontaneous activity and require Mg-nucleotides for activation. Structural mechanisms underlying these properties are unknown. Here, we determined cryogenic electron microscopy structures of vascular KATP channels bound to inhibitory ATP and glibenclamide, which differ informatively from similarly determined pancreatic KATP channel isoform (Kir6.2/SUR1). Unlike SUR1, SUR2B subunits adopt distinct rotational "propeller" and "quatrefoil" geometries surrounding their Kir6.1 core. The glutamate/aspartate-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. Molecular dynamics simulations reveal MgADP-dependent dynamic tripartite interactions between this linker, SUR2B, and Kir6.1. The structures captured implicate a progression of intermediate states between MgADP-free inactivated, and MgADP-bound activated conformations wherein the glutamate/aspartate-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation.

Original languageEnglish (US)
Article numbere2109441118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number44
DOIs
StatePublished - Nov 2 2021

Keywords

  • ABC transporter
  • ATP-sensitive potassium channel
  • Cantu syndrome
  • Kir6.1
  • Sulfonylurea receptor 2B

ASJC Scopus subject areas

  • General

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