Structure of a β1-adrenergic G-protein-coupled receptor

Tony Warne, Maria J. Serrano-Vega, Jillian G. Baker, Rouslan Moukhametzianov, Patricia C. Edwards, Richard Henderson, Andrew G. W. Leslie, Christopher G. Tate () and Gebhard F. X. Schertler ()
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Tony Warne: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Maria J. Serrano-Vega: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Jillian G. Baker: Institute of Cell Signalling, Medical School, Queen’s Medical Centre, University of Nottingham
Rouslan Moukhametzianov: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Patricia C. Edwards: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Richard Henderson: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Andrew G. W. Leslie: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Christopher G. Tate: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Gebhard F. X. Schertler: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK

Nature, 2008, vol. 454, issue 7203, 486-491

Abstract: Abstract G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 Å resolution crystal structure of a β1-adrenergic receptor in complex with the high-affinity antagonist cyanopindolol. The modified turkey (Meleagris gallopavo) receptor was selected to be in its antagonist conformation and its thermostability improved by earlier limited mutagenesis. The ligand-binding pocket comprises 15 side chains from amino acid residues in 4 transmembrane α-helices and extracellular loop 2. This loop defines the entrance of the ligand-binding pocket and is stabilized by two disulphide bonds and a sodium ion. Binding of cyanopindolol to the β1-adrenergic receptor and binding of carazolol to the β2-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the β2-adrenergic receptor, directly interacts by means of a tyrosine with the highly conserved DRY motif at the end of helix 3 that is essential for receptor activation.

Date: 2008
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DOI: 10.1038/nature07101

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