Evidence for dimerization in the beta(2)-adrenergic receptor from the evolutionary trace method

George V. Gkoutos, Christopher Higgs, Robert P. Bywater, Paul R. Gouldson, Christopher A. Reynolds

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The evolutionary trace method (Lichtarge et al., Proc Natl Acad Sci USA 1996, 93, 7507) was applied to the adrenergic-receptor sequences. The conserved and "conserved-in-class" residues were determined for successive splits along the phylogenetic tree. These residues were then plotted on the internal and external faces of a model of the β2-adrenergic receptor. The adrenergic-receptor model was constructed using knowledge of the helix-helix packing angles in the cryoelectron microscopy structure of rhodopsin and the ideal ridges-in-grooves helix packing patterns known to reproduce these angles. Two clusters were observed on the external (lipid-facing) surface of the receptor model: a major one on helices 5 and 6 and a minor one on helices 2 and 3. The importance of some of the residues on helices 5 and 6 was confirmed by site-direceted mutagenesis. In contrast, very few residues were plotted on the external face of helices 1, 4, or 7. The major cluster is consistent with the dimerization interface in G-protein-coupled receptor domain-swapped dimers, which is proposed to occur between helices 5 and 6. The minor cluster is of unknown function. The clusters on the internal faces contain the known ligand-binding sites, as determined by site-directed mutagenesis. In particular, there is a line of conserved residues on helices 2-7 at a depth of about 14 Å. On helices 2 and 3, and on 6 and 7, the cluster extends considerably deeper than the known binding site. These deeper clusters contain the conserved DRY and NPXXY motifs on helices 3 and 7, respectively, and so are probably related to receptor activation.

Original languageEnglish
Pages (from-to)371-379
Number of pages9
JournalInternational Journal of Quantum Chemistry
Volume74
Issue number3
Early online date6 Jul 1999
DOIs
Publication statusPublished - 1999
Externally publishedYes

ASJC Scopus subject areas

  • Atomic and Molecular Physics, and Optics
  • Condensed Matter Physics
  • Physical and Theoretical Chemistry

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