 |
PDBsum entry 4py0
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Membrane protein
|
PDB id
|
|
|
|
4py0
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Agonist-Bound structure of the human p2y12 receptor.
|
|
|
Authors
|
|
J.Zhang,
K.Zhang,
Z.G.Gao,
S.Paoletta,
D.Zhang,
G.W.Han,
T.Li,
L.Ma,
W.Zhang,
C.E.Müller,
H.Yang,
H.Jiang,
V.Cherezov,
V.Katritch,
K.A.Jacobson,
R.C.Stevens,
B.Wu,
Q.Zhao.
|
|
|
Ref.
|
|
Nature, 2014,
509,
119-122.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The P2Y12 receptor (P2Y12R), one of eight members of the P2YR family expressed
in humans, is one of the most prominent clinical drug targets for inhibition of
platelet aggregation. Although mutagenesis and modelling studies of the P2Y12R
provided useful insights into ligand binding, the agonist and antagonist
recognition and function at the P2Y12R remain poorly understood at the molecular
level. Here we report the structures of the human P2Y12R in complex with the
full agonist 2-methylthio-adenosine-5'-diphosphate (2MeSADP, a close analogue of
endogenous agonist ADP) at 2.5 Å resolution, and the corresponding ATP
derivative 2-methylthio-adenosine-5'-triphosphate (2MeSATP) at 3.1 Å
resolution. These structures, together with the structure of the P2Y12R with
antagonist ethyl
6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate
(AZD1283), reveal striking conformational changes between nucleotide and
non-nucleotide ligand complexes in the extracellular regions. Further analysis
of these changes provides insight into a distinct ligand binding landscape in
the δ-group of class A G-protein-coupled receptors (GPCRs). Agonist and
non-nucleotide antagonist adopt different orientations in the P2Y12R, with only
partially overlapped binding pockets. The agonist-bound P2Y12R structure answers
long-standing questions surrounding P2Y12R-agonist recognition, and reveals
interactions with several residues that had not been reported to be involved in
agonist binding. As a first example, to our knowledge, of a GPCR in which
agonist access to the binding pocket requires large-scale rearrangements in the
highly malleable extracellular region, the structural and docking studies will
therefore provide invaluable insight into the pharmacology and mechanisms of
action of agonists and different classes of antagonists for the P2Y12R and
potentially for other closely related P2YRs.
|
|
|
|
|
|
|
