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Ligand binding and subtype selectivity of the human A(2A) adenosine receptor: identification and characterization of essential amino acid residues

Academic Article
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Overview

authors

  • Jaakola, V. P.
  • Lane, J. R.
  • Lin, J. Y.
  • Katritch, Vsevolod
  • Ijzerman, A. P.
  • Stevens, Raymond

publication date

  • April 2010

journal

  • Journal of Biological Chemistry  Journal

abstract

  • The crystal structure of the human A(2A) adenosine receptor bound to the A(2A) receptor-specific antagonist, ZM241385, was recently determined at 2.6-A resolution. Surprisingly, the antagonist binds in an extended conformation, perpendicular to the plane of the membrane, and indicates a number of interactions unidentified before in ZM241385 recognition. To further understand the selectivity of ZM241385 for the human A(2A) adenosine receptor, we examined the effect of mutating amino acid residues within the binding cavity likely to have key interactions and that have not been previously examined. Mutation of Phe-168 to Ala abolishes both agonist and antagonist binding as well as receptor activity, whereas mutation of this residue to Trp or Tyr had only moderate effects. The Met-177 --> Ala mutation impeded antagonist but not agonist binding. Finally, the Leu-249 --> Ala mutant showed neither agonist nor antagonist binding affinity. From our results and previously published mutagenesis data, we conclude that conserved residues Phe-168(5.29), Glu-169(5.30), Asn-253(6.55), and Leu-249(6.51) play a central role in coordinating the bicyclic core present in both agonists and antagonists. By combining the analysis of the mutagenesis data with a comparison of the sequences of different adenosine receptor subtypes from different species, we predict that the interactions that determine subtype selectivity reside in the more divergent "upper" region of the binding cavity while the "lower" part of the binding cavity is conserved across adenosine receptor subtypes.

subject areas

  • Adenosine A2 Receptor Antagonists
  • Amino Acid Substitution
  • Binding Sites
  • Cell Line
  • Humans
  • Ligands
  • Models, Molecular
  • Mutagenesis
  • Mutation, Missense
  • Protein Binding
  • Receptor, Adenosine A2A
  • Triazines
  • Triazoles
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Identity

PubMed Central ID

  • PMC2857108

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M109.096974

PubMed ID

  • 20147292
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Additional Document Info

start page

  • 13032

end page

  • 13044

volume

  • 285

issue

  • 17

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