PT  - JOURNAL ARTICLE
AU  - Min Woo Sung
AU  - Zhongying Yang
AU  - Bruce L. Patton
AU  - Barmak Mostofian
AU  - John Russo
AU  - Daniel M. Zuckerman
AU  - Show-Ling Shyng
TI  - Vascular K<sub>ATP</sub> channel structural dynamics reveal regulatory mechanism by Mg-nucleotides
AID  - 10.1101/2021.05.15.444267
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.15.444267
4099  - http://biorxiv.org/content/early/2021/05/16/2021.05.15.444267.short
4100  - http://biorxiv.org/content/early/2021/05/16/2021.05.15.444267.full
AB  - Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantú 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 the first cryoEM 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 previously unseen ED-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. MD 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 ED-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation.Competing Interest StatementThe authors have declared no competing interest.ABCATP-Binding CassetteCDCytoplasmic DomainCTDC-Terminal DomainGlibGlibenclamideKNtKir6.x N-terminal domainNBDNucleotide Binding DomainTMTransMembraneTMDTransMembrane DomainTMBTransMembrane Bundle