6w86 | pdb_00006w86
K2P2.1 (TREK-1):ML335 complex, 100 mM K+
Structural highlights
Publication Abstract from PubMedK2P potassium channels regulate cellular excitability using their selectivity filter (C-type) gate. C-type gating mechanisms, best characterized in homotetrameric potassium channels, remain controversial and are attributed to selectivity filter pinching, dilation, or subtle structural changes. The extent to which such mechanisms control C-type gating of innately heterodimeric K2Ps is unknown. Here, combining K2P2.1 (TREK-1) x-ray crystallography in different potassium concentrations, potassium anomalous scattering, molecular dynamics, and electrophysiology, we uncover unprecedented, asymmetric, potassium-dependent conformational changes that underlie K2P C-type gating. These asymmetric order-disorder transitions, enabled by the K2P heterodimeric architecture, encompass pinching and dilation, disrupt the S1 and S2 ion binding sites, require the uniquely long K2P SF2-M4 loop and conserved "M3 glutamate network," and are suppressed by the K2P C-type gate activator ML335. These findings demonstrate that two distinct C-type gating mechanisms can operate in one channel and underscore the SF2-M4 loop as a target for K2P channel modulator development. K2P channel C-type gating involves asymmetric selectivity filter order-disorder transitions.,Lolicato M, Natale AM, Abderemane-Ali F, Crottes D, Capponi S, Duman R, Wagner A, Rosenberg JM, Grabe M, Minor DL Jr Sci Adv. 2020 Oct 30;6(44). pii: 6/44/eabc9174. doi: 10.1126/sciadv.abc9174., Print 2020 Oct. PMID:33127683[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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