A lower X-gate in TASK channels traps inhibitors within the vestibule

DOI: 10.1038/s41586-020-2250-8

Authors: Karin E. J. Roedstroem (Structural Genomics Consortium, University of Oxford) , Aytuğ K. Kiper (University of Marburg) , Wei Zhang (Institute of Microbiology, Chinese Academy of Sciences; Structural Genomics Consortium, University of Oxford) , Susanne Rinné (University of Marburg) , Ashley C. W. Pike (Structural Genomics Consortium, University of Oxford) , Matthias Goldstein (University of Marburg) , Linus J. Conrad (University of Sheffield; University of Oxford) , Martina Delbeck (Bayer AG) , Michael G. Hahn (Bayer AG) , Heinrich Meier (Bayer AG) , Magdalena Platzk (Bayer AG) , Andrew Quigley (Structural Genomics Consortium, University of Oxford) , David Speedman (Structural Genomics Consortium, University of Oxford) , Leela Shrestha (Structural Genomics Consortium, University of Oxford) , Shubhashish M. M. Mukhopadhyay (Structural Genomics Consortium, University of Oxford) , Nicola A. Burgess-Brown (Structural Genomics Consortium, University of Oxford) , Stephen J. Tucker (University of Oxford) , Thomas Müller (Bayer AG) , Niels Decher (University of Marburg) , Elisabeth P. Carpenter (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature , VOL 18

State: Published (Approved)
Published: April 2020

Abstract: TWIK-related acid-sensitive potassium (TASK) channels—members of the two pore domain potassium (K2P) channel family—are found in neurons, cardiomyocytes and vascular smooth muscle cells, where they are involved in the regulation of heart rate, pulmonary artery tone, sleep/wake cycles8 and responses to volatile anaesthetics. K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli. Unlike other K2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation. In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below; however, the K2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate—which we designate as an ‘X-gate’—created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues (243VLRFMT248) that are essential for responses to volatile anaesthetics, neurotransmitters and G-protein-coupled receptors. Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders.

Journal Keywords: Ion channels in the nervous system; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 14/05/2020 13:27

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)