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Nature. 2015 Jul 30;523(7562):561-7. doi: 10.1038/nature14656. Epub 2015 Jul 22.

Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser.

Author information

1
Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
2
Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA.
3
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
4
Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany.
5
Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA.
6
1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
7
The National Resource for Automated Molecular Microscopy, New York Structural Biology Center, New York, New York 10027, USA.
8
Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA.
9
Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA.
10
Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
11
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA.
12
Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA.
13
1] Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA [2] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA.
14
1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, Arizona State University, Tempe, Arizona 85287, USA.
15
1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Beijing Computational Science Research Center, Haidian District, Beijing 10084, China.
16
1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA.
17
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
18
Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
19
Swiss Light Source at Paul Scherrer Institute, CH-5232 Villigen, Switzerland.
20
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
21
School of Medicine and School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
22
1] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA [2] Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA.
23
Laboratory of Biomolecular Research at Paul Scherrer Institute, CH-5232 Villigen, Switzerland.
24
Department of Biology, Universität Konstanz, 78457 Konstanz, Germany.
25
Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
26
1] Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany [2] Centre for Ultrafast Imaging, 22761 Hamburg, Germany.
27
1] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
28
1] Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [2] Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China.
29
1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Abstract

G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ∼20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.

PMID:
26200343
PMCID:
PMC4521999
DOI:
10.1038/nature14656
[Indexed for MEDLINE]
Free PMC Article

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