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Science. 2015 Mar 13;347(6227):1256-9. doi: 10.1126/science.1261512.

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

Author information

1
Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
2
Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
3
Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK.
4
Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
5
Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
6
Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
7
Pfizer Neusentis, Granta Park, Cambridge CB21 6GS, UK.
8
OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
9
Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. liz.carpenter@sgc.ox.ac.uk stephen.tucker@physics.ox.ac.uk.
10
Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. liz.carpenter@sgc.ox.ac.uk stephen.tucker@physics.ox.ac.uk.

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.

PMID:
25766236
PMCID:
PMC6034649
DOI:
10.1126/science.1261512
[Indexed for MEDLINE]
Free PMC Article

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