1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
2. Institute of Cell Signalling, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK

Correspondence to: Christopher G. Tate¹Gebhard F. X. Schertler¹ Correspondence and requests for materials should be addressed to C.G.T. (Email: cgt@mrc-lmb.cam.ac.uk) or G.F.X.S. (Email: gfx@mrc-lmb.cam.ac.uk).

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 ₁-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 -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 ₁-adrenergic receptor and binding of carazolol to the ₂-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the ₂-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.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.