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Title: K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site

Abstract

Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK1 subfamily generate ‘leak’ currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses1, 2, 3. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit4, 5, 6. In contrast to other potassium channels, K2P channels use a selectivity filter ‘C-type’ gate7, 8, 9, 10 as the principal gating site. Despite recent advances3, 11, 12, poor pharmacological profiles of K2P channels limit mechanistic and biological studies. Here we describe a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges that restrict interdomain interface movement behind the selectivity filter. Structures of K2P2.1 (also known as TREK-1) alone and with two selective K2P2.1 (TREK-1) and K2P10.1 (TREK-2) activators—an N-aryl-sulfonamide, ML335, and a thiophene-carboxamide, ML402—define a cryptic binding pocket unlike other ion channel small-molecule binding sites and, together with functional studies, identify a cation–π interaction that controls selectivity. Together, our data reveal a druggable K2P site that stabilizes the C-type gate ‘leak mode’ and provide direct evidence for K2P selectivity filter gating.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
AHA
OSTI Identifier:
1372255
Resource Type:
Journal Article
Journal Name:
Nature (London)
Additional Journal Information:
Journal Volume: 547; Journal Issue: 7663; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Lolicato, Marco, Arrigoni, Cristina, Mori, Takahiro, Sekioka, Yoko, Bryant, Clifford, Clark, Kimberly A., and Minor, Daniel L. K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site. United States: N. p., 2017. Web. doi:10.1038/nature22988.
Lolicato, Marco, Arrigoni, Cristina, Mori, Takahiro, Sekioka, Yoko, Bryant, Clifford, Clark, Kimberly A., & Minor, Daniel L. K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site. United States. doi:10.1038/nature22988.
Lolicato, Marco, Arrigoni, Cristina, Mori, Takahiro, Sekioka, Yoko, Bryant, Clifford, Clark, Kimberly A., and Minor, Daniel L. Mon . "K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site". United States. doi:10.1038/nature22988.
@article{osti_1372255,
title = {K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site},
author = {Lolicato, Marco and Arrigoni, Cristina and Mori, Takahiro and Sekioka, Yoko and Bryant, Clifford and Clark, Kimberly A. and Minor, Daniel L.},
abstractNote = {Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK1 subfamily generate ‘leak’ currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses1, 2, 3. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit4, 5, 6. In contrast to other potassium channels, K2P channels use a selectivity filter ‘C-type’ gate7, 8, 9, 10 as the principal gating site. Despite recent advances3, 11, 12, poor pharmacological profiles of K2P channels limit mechanistic and biological studies. Here we describe a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges that restrict interdomain interface movement behind the selectivity filter. Structures of K2P2.1 (also known as TREK-1) alone and with two selective K2P2.1 (TREK-1) and K2P10.1 (TREK-2) activators—an N-aryl-sulfonamide, ML335, and a thiophene-carboxamide, ML402—define a cryptic binding pocket unlike other ion channel small-molecule binding sites and, together with functional studies, identify a cation–π interaction that controls selectivity. Together, our data reveal a druggable K2P site that stabilizes the C-type gate ‘leak mode’ and provide direct evidence for K2P selectivity filter gating.},
doi = {10.1038/nature22988},
journal = {Nature (London)},
issn = {0028-0836},
number = 7663,
volume = 547,
place = {United States},
year = {2017},
month = {7}
}

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