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GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function

Academic Article
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Overview

authors

  • Rosenbaum, D. M.
  • Cherezov, Vadim
  • Hanson, Michael
  • Rasmussen, S. G. F.
  • Thian, F. S.
  • Kobilka, T. S.
  • Choi, H. J.
  • Yao, X. J.
  • Weis, W. I.
  • Stevens, Raymond
  • Kobilka, B. K.

publication date

  • November 2007

journal

  • Science  Journal

abstract

  • The beta2-adrenergic receptor (beta2AR) is a well-studied prototype for heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) that respond to diffusible hormones and neurotransmitters. To overcome the structural flexibility of the beta2AR and to facilitate its crystallization, we engineered a beta2AR fusion protein in which T4 lysozyme (T4L) replaces most of the third intracellular loop of the GPCR ("beta2AR-T4L") and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of beta2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting a conformational pathway from the ligand-binding pocket to regions that interact with G proteins.

subject areas

  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Amino Acid Sequence
  • Bacteriophage T4
  • Binding Sites
  • Cell Line
  • Cell Membrane
  • Crystallization
  • Crystallography, X-Ray
  • Drug Inverse Agonism
  • Humans
  • Immunoglobulin Fab Fragments
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Muramidase
  • Propanolamines
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Adrenergic, beta-2
  • Recombinant Fusion Proteins
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Identity

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1150609

PubMed ID

  • 17962519
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Additional Document Info

start page

  • 1266

end page

  • 1273

volume

  • 318

issue

  • 5854

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