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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	A pharmacological master key mechanism that unlocks the selectivity filter gate in K + channels Marcus Schewe , Han Sun , Ümit Mert , Alexandra Mackenzie , Ashley C. W. Pike , Friederike Schulz , Cristina Constantin , Kirsty S. Vowinkel , Linus J. Conrad , Aytug K. Kiper , Wendy Gonzalez , Marianne Musinszki , Marie Tegtmeier , David C. Pryde , Hassane Belabed , Marc Nazare , Bert L. De Groot , Niels Decher , Bernd Fakler , Elisabeth P. Carpenter , Stephen J. Tucker , Thomas Baukrowitz Science 363, 875 - 880 DOI: 10.1126/science.aav0569 Diamond Proposal Number(s): [8421] Show Abstract ▼ Abstract: Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+ channels gated at their selectivity filter (SF), including many two-pore domain K+ (K2P) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca2+)–activated big-conductance potassium (BK)–type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+ occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+ channel activators and highlight a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design.	Feb 2019

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I03-Macromolecular Crystallography

A pharmacological master key mechanism that unlocks the selectivity filter gate in K + channels