Vascular K ATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides
| Autor: | Zhongying Yang, Bruce L. Patton, Min Woo Sung, Camden M. Driggers, Daniel M. Zuckerman, John D. Russo, Show-Ling Shyng, Barmak Mostofian |
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| Rok vydání: | 2021 |
| Předmět: |
Gene isoform
chemistry.chemical_classification endocrine system Multidisciplinary ATP-sensitive potassium channel Chemistry Glutamate receptor ATP-binding cassette transporter Inhibitory postsynaptic potential Glibenclamide medicine Biophysics Nucleotide Linker hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 118 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2109441118 |
| Popis: | Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantu 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. |
| Databáze: | OpenAIRE |
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