Evidence for dimerization in the β2-adrenergic receptor from the evolutionary trace method

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

Allbwn ymchwil: Cyfraniad at gyfnodolynErthygladolygiad gan gymheiriaid

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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 β 2-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.

Iaith wreiddiolSaesneg
Tudalennau (o-i)371-379
Nifer y tudalennau9
CyfnodolynInternational Journal of Quantum Chemistry
Cyfrol74
Rhif cyhoeddi3
Dyddiad ar-lein cynnar06 Gorff 1999
Dynodwyr Gwrthrych Digidol (DOIs)
StatwsCyhoeddwyd - 15 Awst 1999

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