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

DOI: 10.1126/science.aav0569

Authors: Marcus Schewe (Christian-Albrechts University of Kiel) , Han Sun (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)) , Ümit Mert (Christian-Albrechts University of Kiel) , Alexandra Mackenzie (Structural Genomics Consortium, University of Oxford; OXION Initiative in Ion Channels and Disease) , Ashley C. W. Pike (Structural Genomics Consortium, University of Oxford) , Friederike Schulz (Christian-Albrechts University of Kiel) , Cristina Constantin (Albert-Ludwigs University of Freiburg; Centers for Biological Signaling Studies CIBSS and BIOSS) , Kirsty S. Vowinkel (Philipps-University of Marburg) , Linus J. Conrad (OXION Initiative in Ion Channels and Disease, University of Oxford) , Aytug K. Kiper (Philipps-University of Marburg) , Wendy Gonzalez (Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca) , Marianne Musinszki (Christian-Albrechts University of Kiel) , Marie Tegtmeier (Christian-Albrechts University of Kiel) , David C. Pryde (Pfizer Worldwide Medicinal Chemistry) , Hassane Belabed (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)) , Marc Nazare (Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)) , Bert L. De Groot (Max Planck Institute for Biophysical Chemistry) , Niels Decher (Philipps-University of Marburg) , Bernd Fakler (Albert-Ludwigs University of Freiburg; Centers for Biological Signaling Studies CIBSS and BIOSS) , Elisabeth P. Carpenter (Structural Genomics Consortium, University of Oxford; OXION Initiative in Ion Channels and Disease) , Stephen J. Tucker (OXION Initiative in Ion Channels and Disease, University of Oxford) , Thomas Baukrowitz (Christian-Albrechts University of Kiel)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Science , VOL 363 , PAGES 875 - 880

State: Published (Approved)
Published: February 2019
Diamond Proposal Number(s): 8421

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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 26/09/2019 15:48

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)