K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac

DOI: 10.1126/science.1261512
PMID: 25766236

Authors: Y. Y. Dong (Structural Genomics Consortium, University of Oxford) , A. Pike (University of Oxford) , A. Mackenzie (University of Oxford) , C. Mcclenaghan (University of Oxford) , P. Aryal (University of Oxford) , L. Dong (Structural Genomics Consortium, University of Oxford) , A. Quigley (University of Oxford) , M. Grieben (University of Oxford) , S. Goubin (Structural Genomics Consortium, University of Oxford) , S. Mukhopadhyay (Structural Genomics Consortium, University of Oxford) , G. F. Ruda (Structural Genomics Consortium, University of Oxford) , M. V. Clausen (University of Oxford) , L. Cao (Pfizer Neusentis) , P. E. Brennan (Structural Genomics Consortium, University of Oxford) , N. A. Burgess-Brown (Structural Genomics Consortium, University of Oxford) , M. S. P. Sansom (University of Oxford) , S. J. Tucker (University of Oxford) , E. P. Carpenter (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 347 (6227) , PAGES 1256 - 1259

State: Published (Approved)
Published: March 2015
Diamond Proposal Number(s): 8421 , 10619

Abstract: TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.

Journal Keywords: Arachidonic; Binding; Crystallography; X-Ray; Fluoxetine; Humans; Ion; Models; Molecular;Potassium; Potassium; Tandem; Protein; Secondary; Protein; Tertiary

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


Instruments: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 30/03/2015 09:17

Discipline Tags:

Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)