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

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      1 , 1 , 1 , 1 , 2 , 3 , 5 , 5 , 5 , 3 , 6 , 1 , 1 , 1 , 7 , 1 , 8 , 9 , 9 , 10 , 11 , 11 , 12 , 12 , 1 , 1 , 1 , 1 , 1 , 13 , 13 , 13 , 14 , 5 , 2 , 15 , 2 , 15 , 2 , 15 , 2 , 15 , 2 , 15 , 2 , 2 , 2 , 16 , 2 , 2 , 17 , 2 , 2 , 18 , 18 , 18 , 7 , 19 , 4 , 20 , 20 , 14 , 21 , 22 , 23 , 24 , 8 , 8 , 20 , 18 , 5 , 25 , 2 , 15 , 2 , 2 , 15 , 11 , 26 , 4 , 12 , 9 , 10 , 3 , 4 , 27 , 3 , 1 , 1 , 28

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          Abstract

          G protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signaling 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 TM7 and Helix 8 to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ~20° rotation between the N- and C- 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 signaling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.

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          Most cited references 84

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          High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor.

          Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human beta2-adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the beta2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.
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            Linking crystallographic model and data quality.

            In macromolecular x-ray crystallography, refinement R values measure the agreement between observed and calculated data. Analogously, R(merge) values reporting on the agreement between multiple measurements of a given reflection are used to assess data quality. Here, we show that despite their widespread use, R(merge) values are poorly suited for determining the high-resolution limit and that current standard protocols discard much useful data. We introduce a statistic that estimates the correlation of an observed data set with the underlying (not measurable) true signal; this quantity, CC*, provides a single statistically valid guide for deciding which data are useful. CC* also can be used to assess model and data quality on the same scale, and this reveals when data quality is limiting model improvement.
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              Crystal structure of rhodopsin: A G protein-coupled receptor.

              Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) respond to a variety of different external stimuli and activate G proteins. GPCRs share many structural features, including a bundle of seven transmembrane alpha helices connected by six loops of varying lengths. We determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution. The highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the seven-helix transmembrane motif. The ground-state chromophore, 11-cis-retinal, holds the transmembrane region of the protein in the inactive conformation. Interactions of the chromophore with a cluster of key residues determine the wavelength of the maximum absorption. Changes in these interactions among rhodopsins facilitate color discrimination. Identification of a set of residues that mediate interactions between the transmembrane helices and the cytoplasmic surface, where G-protein activation occurs, also suggests a possible structural change upon photoactivation.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                17 June 2015
                22 July 2015
                30 July 2015
                30 January 2016
                : 523
                : 7562
                : 561-567
                Affiliations
                [1 ]Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, MI 49503, USA
                [2 ]Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287-1604, USA
                [3 ]Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA
                [4 ]Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA
                [5 ]Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany
                [6 ]Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA
                [7 ]Department of Obstetrics & Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
                [8 ]The National Resource for Automated Molecular Microscopy, New York Structural Biology Center, New York, NY 10027, USA
                [9 ]Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA
                [10 ]Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA
                [11 ]Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
                [12 ]Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
                [13 ]Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA
                [14 ]BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, NY 14203, USA
                [15 ]Department of Physics, Arizona State University, Tempe, AZ 85287, USA
                [16 ]Beijing Computational Science Research Center, Haidian District, Beijing 10084, China
                [17 ]Department of Physics, University of Wisconsin - Milwaukee, Milwaukee WI 53211, USA
                [18 ]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
                [19 ]Swiss Light Source at Paul Scherrer Institute, CH-5232 Villigen, Switzerland
                [20 ]School of Medicine and School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
                [21 ]Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA
                [22 ]Laboratory of Biomolecular Research at Paul Scherrer Institute, CH-5232 Villigen, Switzerland
                [23 ]Department of Biology, Universität Konstanz, 78457 Konstanz, Germany
                [24 ]Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
                [25 ]Centre for Ultrafast Imaging, 22761 Hamburg, Germany
                [26 ]Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
                [27 ]iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai, 201210, China
                [28 ]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
                Author notes
                [§ ]Correspondence to H. Eric Xu: Eric.Xu@ 123456vai.org
                [*]

                These authors contributed equally.

                Article
                NIHMS700709
                10.1038/nature14656
                4521999
                26200343
                c1ed0ccc-2465-4b2c-a7ab-e177cbc14b9b

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