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

2008; Nature Portfolio; Volume: 454; Issue: 7203 Linguagem: Inglês

10.1038/nature07101

1476-4687

Tony Warne, María J. Serrano‐Vega, Jillian G. Baker, R. Moukhametzianov, Patricia C. Edwards, Richard A. Henderson, Andrew G. W. Leslie, Christopher G. Tate, Gebhard F. X. Schertler,

Mass Spectrometry Techniques and Applications

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. The adrenalin stress hormone receptor (β1 adrenergic receptor or β1AR) regulates heart rate and blood pressure and is the target for β-blockers. Like other members of the G-protein-coupled receptor family, it is difficult to purify. But the form of the enzyme found in the turkey is more stable than the human equivalent, and by using that, and mutagenesis to thermostabilize the receptor, β1AR has been crystallized bound to the β-blocker cyano-pindolol. The structure reveals insights into the G-protein-binding interface.