5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Structural and Functional Analysis of a β 2-Adrenergic Receptor Complex with GRK5

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          SUMMARY

          The phosphorylation of agonist-occupied G protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry, electron microscopy, mutagenesis, molecular dynamics simulations and computational docking to analyze GRK5 interaction with the β 2-adrenergic receptor (β 2AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C-terminus of the β 2AR with the GRK5 RH bundle subdomain, membrane-binding surface and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs.

          e-TOC

          Biophysical analysis of a G protein-coupled receptor (GPCR) complex with a GPCR kinase reveals significant conformational changes in the kinase that are essential for effective receptor phosphorylation.

          Related collections

          Author and article information

          Journal
          0413066
          2830
          Cell
          Cell
          Cell
          0092-8674
          1097-4172
          19 April 2017
          20 April 2017
          20 April 2018
          : 169
          : 3
          : 407-421.e16
          Affiliations
          [1 ]Department of Biochemistry and Molecular Biology and the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
          [2 ]Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA
          [3 ]Sungkyunkwan University, School of Pharmacy, Suwon, 16419, South Korea
          [4 ]Department of Computer Science, Department of Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA
          [5 ]Biophysics Program, Stanford University, Stanford, CA 94305, USA
          [6 ]Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University School of Medicine, Stanford, CA 94305, USA
          [7 ]Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
          Author notes
          [8]

          Co-first author

          [9]

          Co-senior author

          [10]

          Lead Contact

          Article
          PMC5526774 PMC5526774 5526774 nihpa865358
          10.1016/j.cell.2017.03.047
          5526774
          28431242
          c1d8ecc8-9bae-491b-993b-4406bf9cdbc4
          History
          Categories
          Article

          Comments

          Comment on this article