Details

Autor(en) / Beteiligte

• Zhang, Jin
• Zhang, Kaihua
• Gao, Zhan-Guo
• Paoletta, Silvia
• Zhang, Dandan
• Han, Gye Won
• Li, Tingting
• Ma, Limin
• Zhang, Wenru
• Müller, Christa E.
• Yang, Huaiyu
• Jiang, Hualiang
• Cherezov, Vadim
• Katritch, Vsevolod
• Jacobson, Kenneth A.
• Stevens, Raymond C.
• Wu, Beili
• Zhao, Qiang

Titel

Agonist-bound structure of the human P2Y12 receptor

Ist Teil von

• Nature (London), 2014-05, Vol.509 (7498), p.119-122

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2014

Quelle

EBSCOhost Psychology and Behavioral Sciences Collection

Beschreibungen/Notizen

• An X-ray structure of human P2Y 12 receptor, a clinical drug target for platelet aggregation inhibitors, is presented in complex with an agonist, providing insight into the δ-group of class A G-protein-coupled receptors. Key platelet aggregation GPCR structures Two papers in this issue of Nature present the crystal structures of the human P2Y 12 receptor, first in complex with the antithrombotic drug AZD1283, and second, bound to a full agonist (a close analogue of endogenous agonist ADP) and to a partial agonist. P2Y receptors are a family of purinergic G-protein-coupled receptors (GPCRs) that are activated by extracellular nucleotides. The P2Y 12 receptor is found mainly on the surface of platelets, where it regulates platelet activation and thrombus formation, and it is the target of several important antithrombotic drugs. In overall structure, P2Y 12 receptor is found to be similar to other GPCRs, although both the shape and location of the ligand-binding pocket are unusual. Comparisons of the three newly determined structures reveal that agonist binding induces a large-scale rearrangement of the extracellular domains of the GPCR. The P2Y 12 receptor (P2Y 12 R), 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 P2Y 12 R provided useful insights into ligand binding 1 , 2 , 3 , 4 , the agonist and antagonist recognition and function at the P2Y 12 R remain poorly understood at the molecular level. Here we report the structures of the human P2Y 12 R 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 P2Y 12 R with antagonist ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) 5 , 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 P2Y 12 R, with only partially overlapped binding pockets. The agonist-bound P2Y 12 R structure answers long-standing questions surrounding P2Y 12 R–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 P2Y 12 R and potentially for other closely related P2YRs.