The group of Daniel Minor in the Cardiovascular Research Institute at the University of California San Francisco determined crystal structures of the mechano- and thermo sensitive K2P potassium channel, K2P2.1 (TREK-1), alone and as complexes with two novel small molecule activators, ML335 and ML402. TREK channels influence temperature perception, recovery from ischemia, anesthetic responses, and pain. Similar to many ion channels, K2P channels lack a well-developed pharmacology that limits mechanistic and biological investigations. The TREK-1 structures show how small molecules can control K2P function and revealed a previously unknown, cryptic binding site, termed the 'K2P modulator pocket', located behind the channel selectivity filter. Unlike other channels, the K2P selectivity filter serves as the primary site of channel gating. The structures revealed that both activators bind in a "modulator' site that is hidden in the absence of the compounds and function like molecular wedges that stabilize the channel selectivity filter gate. The modulator pocket is unlike any other described for an ion channel and presents a novel target for developing K2P-selective small molecules. As TREK channel activation should limit nerve excitation, such molecules may offer new avenues for the treatment of chronic pain.
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Figure: ML335 is shown bound to the TREK-1 dimer, with subunits (green and orange) in ribbon form, the backbone selectivity filter (SF) as sticks, and ML335 (yellow) and potassium ions (magenta) as spheres. The chemical structures of ML335 and ML402 on the right indicate the 'upper' and 'lower' rings. |
Citation: Lolicato, M, Arrigoni, C, Mori, T, Sekioka, Y, Bryant, C, Clark, KA, Minor, Jr , DL. K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site, Nature 547, 364-368 (2017). DOI: 10.1038/nature22988
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