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Conformational states of the full-length glucagon receptor

Academic Article
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Overview

related to degree

  • Wang, Chong, Ph.D. in Chemistry, Scripps Research , transferred from UCSD 2011 - 2014

authors

  • Yang, L.
  • Yang, D.
  • de Graaf, C.
  • Moeller, A.
  • West, G. M.
  • Dharmarajan, V.
  • Wang, Chong
  • Siu, F. Y.
  • Song, G.
  • Reedtz-Runge, S.
  • Pascal, B. D.
  • Wu, B.
  • Potter, Clinton
  • Zhou, H.
  • Griffin, Patrick
  • Carragher, Bridget
  • Yang, H.
  • Wang, M. W.
  • Stevens, Raymond
  • Jiang, H.

publication date

  • July 2015

journal

  • Nature Communications  Journal

abstract

  • Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, and their signalling is regulated by peptide hormones. Using a hybrid structural biology approach together with the ECD and 7TM domain crystal structures of the glucagon receptor (GCGR), we examine the relationship between full-length receptor conformation and peptide ligand binding. Molecular dynamics (MD) and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. The electron microscopy (EM) map of the full-length GCGR shows how a monoclonal antibody stabilizes the ECD and 7TM domain in an elongated conformation. Hydrogen/deuterium exchange (HDX) studies and MD simulations indicate that an open conformation is also stabilized by peptide ligand binding. The combined studies reveal the open/closed states of GCGR and suggest that glucagon binds to GCGR by a conformational selection mechanism.

subject areas

  • Animals
  • Chromatography, Liquid
  • Deuterium Exchange Measurement
  • Disulfides
  • Glucagon
  • Humans
  • Ligands
  • Microscopy, Electron
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Glucagon
  • Sf9 Cells
  • Tandem Mass Spectrometry
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Identity

PubMed Central ID

  • PMC4532856

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms8859

PubMed ID

  • 26227798
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Additional Document Info

start page

  • 7859

volume

  • 6

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