TY  - JOUR
A1  - Diskowski, Marina
A1  - Mehdipour, Ahmadreza
A1  - Wunnicke, Dorith
A1  - Mills, Deryck J.
A1  - Mikusevic, Vedrana
A1  - Bärland, Natalie
A1  - Hoffmann, Jan
A1  - Morgner, Nina
A1  - Steinhoff, Heinz-Jürgen
A1  - Hummer, Gerhard
A1  - Vonck, Janet
A1  - Hänelt, Inga
T1  - Helical jackknives control the gates of the double-pore K+ uptake system KtrAB
T2  - eLife
N2  - Ion channel gating is essential for cellular homeostasis and is tightly controlled. In some eukaryotic and most bacterial ligand-gated K+ channels, RCK domains regulate ion fluxes. Until now, a single regulatory mechanism has been proposed for all RCK-regulated channels, involving signal transduction from the RCK domain to the gating area. Here, we present an inactive ADP-bound structure of KtrAB from Vibrio alginolyticus, determined by cryo-electron microscopy, which, combined with EPR spectroscopy and molecular dynamics simulations, uncovers a novel regulatory mechanism for ligand-induced action at a distance. Exchange of activating ATP to inactivating ADP triggers short helical segments in the K+-translocating KtrB dimer to organize into two long helices that penetrate deeply into the regulatory RCK domains, thus connecting nucleotide-binding sites and ion gates. As KtrAB and its homolog TrkAH have been implicated as bacterial pathogenicity factors, the discovery of this functionally relevant inactive conformation may advance structure-guided drug development.
KW  - Research article
KW  - Biochemistry
KW  - Biophysics and structural biology
KW  - Ligand-gated ion channel
KW  - Potassium transport
KW  - Cryo-electron microscopy
KW  - Pulsed epr
KW  - Md simulations
KW  - Membrane transport
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44576
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-445760
SN  - 2050-084X
N1  - Copyright Diskowski et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
VL  - 6
IS  - e24303
SP  - 1
EP  - 21
PB  - eLife Sciences Publications
CY  - Cambridge
ER  -