Structure of a beta1-adrenergic G-protein-coupled receptor.
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 A resolution crystal structure of a beta(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 alpha-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 beta(1)-adrenergic receptor and binding of carazolol to the beta(2)-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the beta(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.
Warne
Tony
T
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Serrano-Vega
Maria J
MJ
Baker
Jillian G
JG
Moukhametzianov
Rouslan
R
Edwards
Patricia C
PC
Henderson
Richard
R
Leslie
Andrew G W
AG
Tate
Christopher G
CG
Schertler
Gebhard F X
GF
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010869:Pindolol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D011412:Propanolamines / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D014422:Turkeys
D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D008024:Ligands; D050505:Mutant Proteins; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; C014382:carazolol; C047975:cyanopindolol; D010869:Pindolol