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

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. In conclusion, 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.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [4] ;  [4] ;  [3] ;  [5] ;  [1] ;  [1] ;  [6] ;  [1] ;  [7] ;  [8] ;  [8] ;  [9] ;  [10] more »;  [11] ;  [11] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [12] ;  [12] ;  [13] ;  [4] ;  [14] ;  [14] ;  [14] ;  [14] ;  [2] ;  [2] ;  [2] ;  [15] ;  [2] ;  [16] ;  [2] ;  [2] ;  [17] ;  [17] ;  [17] ;  [18] ;  [19] ;  [20] ;  [21] ;  [21] ;  [22] ;  [23] ;  [24] ;  [25] ;  [7] ;  [7] ;  [21] ;  [17] ;  [26] ;  [14] ;  [2] ;  [14] ;  [27] ;  [20] ;  [11] ;  [8] ;  [9] ;  [28] ;  [3] ;  [1] ;  [29] « less
  1. Van Andel Research Inst. (VARI), Grand Rapids, MI (United States)
  2. Arizona State Univ., Tempe, AZ (United States). Biodesign Inst., Dept. of Chemistry and Biochemistry
  3. Univ. of Southern California, Los Angeles, CA (United States). Bridge Inst., Dept. of Chemistry
  4. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Center for Free-Electron Laser Science
  5. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL), Joint Center for Structural Genomics
  6. Van Andel Research Inst. (VARI), Grand Rapids, MI (United States); National Univ. of Singapore (Singapore). Yong Loo Lin School of Medicine, Dept. of Obstetrics & Gynecology
  7. New York Structural Biology Center (NYSBC), New York, NY (United States)
  8. Scripps Research Inst., Jupiter, FL (United States). Dept. of Molecular Therapeutics
  9. Univ. of California, Los Angeles, CA (United States). Jules Stein Eye Inst.
  10. Univ. of Toronto, ON (Canada). Dept. of Biochemistry
  11. Vanderbilt Univ., Nashville, TN (United States). Dept. of Pharmacology
  12. SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS)
  13. SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS); NSF Science and Technology Center, Buffalo, NY (United States). BioXFEL
  14. Arizona State Univ., Tempe, AZ (United States). Biodesign Inst., Dept. of Chemistry and Biochemistry; Arizona State Univ., Tempe, AZ (United States). Dept. of Physics
  15. Arizona State Univ., Tempe, AZ (United States). Biodesign Inst., Dept. of Chemistry and Biochemistry; Beijing Computational Science Research Center, Beijing (China)
  16. Arizona State Univ., Tempe, AZ (United States). Biodesign Inst., Dept. of Chemistry and Biochemistry; Univ. of Wisconsin-Milwaukee, Milwaukee, WI (United States). Dept. of Physics
  17. Chinese Academy of Sciences, Shanghai (China). Shanghai Inst. of Materia Medica, State Key Lab. of Drug Research
  18. National Univ. of Singapore (Singapore). Yong Loo Lin School of Medicine, Dept. of Obstetrics & Gynecology
  19. Paul Scherrer Inst. (PSI), Villigen (Switzerland). Swiss Light Source
  20. Univ. of Southern California, Los Angeles, CA (United States). Bridge Inst., Dept. of Biological Sciences
  21. Trinity College, Dublin, (Ireland). School of Medicine and School of Biochemistry and Immunology
  22. NSF Science and Technology Center, Buffalo, NY (United States). BioXFEL; Univ. of Chicago, IL (United States). Ben May Dept. for Cancer Research
  23. Paul Scherrer Inst., Villigen (Switzerland). Lab. of Biomolecular Research
  24. Univ. of Konstanz, Konstanz (Germany). Dept. of Biology
  25. Chinese Academy of Sciences (CAS), Beijing (China). Inst. of High Energy Physics, Beijing Synchrotron Radiation Facility
  26. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Center for Free-Electron Laser Science; Centre for Ultrafast Imaging, Hamburg (Germany)
  27. Univ. of Toronto, ON (Canada). Dept. of Biochemistry; Univ. of Toronto, ON (Canada). Dept. of Molecular Genetics
  28. Univ. of Southern California, Los Angeles, CA (United States). Bridge Inst., Dept. of Chemistry; Univ. of Southern California, Los Angeles, CA (United States). Bridge Inst., Dept. of Biological Sciences; ShanghaiTech Univ., Shanghai (China)
  29. Van Andel Research Inst. (VARI), Grand Rapids, MI (United States); Chinese Academy of Sciences (CAS), Shanghai (China). Shanghai Inst. of Materia Medica
Publication Date:
OSTI Identifier:
1260958
Grant/Contract Number:
AC02-76SF00515; AC02-06CH11357; P41GM103393; ACB-12002 2012ZX09301001; 2012CB910403; 2013CB910600; XDB08020303; 1231306
Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 523; Journal Issue: 7562; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Research Org:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY X-ray crystallography; G protein-coupled receptors