Project Details
Projekt
Selectivity filter gating in homomeric and heteromeric K+ channels
Subject Area
Biochemistry
Anatomy and Physiology
Anatomy and Physiology
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 291198853
During the first funding period we discovered a novel pharmacological activation mechanism that provided new insight into the mechanism of selectivity filter (SF) gating in different classes of K+ channels (K2P channels, BK channels and hERG channels). We also characterized the unusual ion flux gating mechanism in TWIK channels and contributed to the identification of an allosteric inhibitor site in TASK-1/3 channels. The generated insight showcases the power of combining functional studies and MD simulations as the central purpose of this Research Unit. Here we propose to investigate the pharmacological and physiological mechanisms that control the (SF) gate in various K+ channels. The specific aims include (1) the characterization of the currently unexplored pharmacological and SF gating properties in heteromeric K2P channels as well as (2) in Slo2, TOK-1 and MthK channels, (3) the more global gating transitions in TREK-1 channels, (4) the role of the proximal C-terminus in K2P channel gating and (5) the coupling between SF and helix bundle crossing gate in various K+ channels. These investigations include electrophysiology (patch clamp and bilayer), mutagenesis (classical and unnatural amino acid) and fluorescence measurements on our side that will be comprehensively complemented by MD simulations performed by H. Sun (P3) and B. de Groot/W. Kopec (P5).
DFG Programme
Research Units
