 |
|
Title
|
|
Structure of a beta1-adrenergic G-protein-coupled receptor.
|
|
|
Authors
|
|
T.Warne,
M.J.Serrano-Vega,
J.G.Baker,
R.Moukhametzianov,
P.C.Edwards,
R.Henderson,
A.G.Leslie,
C.G.Tate,
G.F.Schertler.
|
|
|
Ref.
|
|
Nature, 2008,
454,
486-491.
|
|
|
PubMed id
|
|
|
|
|
|
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 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.
|
|
|
|