Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine

Structure. 2011 Sep 7;19(9):1283-93. doi: 10.1016/j.str.2011.06.014.

Abstract

Methylxanthines, including caffeine and theophylline, are among the most widely consumed stimulant drugs in the world. These effects are mediated primarily via blockade of adenosine receptors. Xanthine analogs with improved properties have been developed as potential treatments for diseases such as Parkinson's disease. Here we report the structures of a thermostabilized adenosine A(2A) receptor in complex with the xanthines xanthine amine congener and caffeine, as well as the A(2A) selective inverse agonist ZM241385. The receptor is crystallized in the inactive state conformation as defined by the presence of a salt bridge known as the ionic lock. The complete third intracellular loop, responsible for G protein coupling, is visible consisting of extended helices 5 and 6. The structures provide new insight into the features that define the ligand binding pocket of the adenosine receptor for ligands of diverse chemotypes as well as the cytoplasmic regions that interact with signal transduction proteins.

MeSH terms

  • Adenosine A2 Receptor Agonists / chemistry*
  • Adenosine A2 Receptor Agonists / pharmacology
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Binding Sites
  • Caffeine / chemistry*
  • Caffeine / pharmacology
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein Stability
  • Protein Structure, Tertiary
  • Receptor, Adenosine A2A / chemistry*
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / metabolism
  • Surface Properties
  • Triazines / chemistry*
  • Triazines / pharmacology
  • Triazoles / chemistry*
  • Triazoles / pharmacology
  • Xanthines / chemistry*
  • Xanthines / pharmacology

Substances

  • Adenosine A2 Receptor Agonists
  • Receptor, Adenosine A2A
  • Triazines
  • Triazoles
  • Xanthines
  • ZM 241385
  • Caffeine
  • 8-(4-((2-aminoethyl)aminocarbonylmethyloxy)phenyl)-1,3-dipropylxanthine

Associated data

  • PDB/3PWH
  • PDB/3REY
  • PDB/3RFM