4PXZ

Crystal structure of P2Y12 receptor in complex with 2MeSADP

Summary for 4PXZ

• Entry DOI: 10.2210/pdb4pxz/pdb
• Related: 4NTJ 4PY0
• Descriptor: P2Y purinoceptor 12, Soluble cytochrome b562, 2-(methylsulfanyl)adenosine 5'-(trihydrogen diphosphate), CHOLESTEROL, ... (6 entities in total)
• Functional Keywords: purinergic receptor p2y12, agonist-bound, g-protein coupled receptor (gpcr), membrane protein, signaling protein-agonist complex, psi-biology, gpcr network, structural genomics, signaling membrane protein, gpcr, platelet activation, membrane
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : Q9H244
• Total number of polymer chains: 1
• Total formula weight: 55284.57

Authors

Zhang, J.,Zhang, K.,Gao, Z.G.,Paoletta, S.,Zhang, D.,Han, G.W.,Li, T.,Ma, L.,Zhang, W.,Muller, C.E.,Yang, H.,Jiang, H.,Cherezov, V.,Katritch, V.,Jacobson, K.A.,Stevens, R.C.,Wu, B.,Zhao, Q.,GPCR Network (GPCR) (deposition date: 2014-03-25, release date: 2014-04-30, Last modification date: 2024-11-20)

Primary citation

Zhang, J.,Zhang, K.,Gao, Z.G.,Paoletta, S.,Zhang, D.,Han, G.W.,Li, T.,Ma, L.,Zhang, W.,Muller, C.E.,Yang, H.,Jiang, H.,Cherezov, V.,Katritch, V.,Jacobson, K.A.,Stevens, R.C.,Wu, B.,Zhao, Q.
Agonist-bound structure of the human P2Y12 receptor
Nature, 509:119-122, 2014

PubMed 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.

PubMed: 24784220
DOI: 10.1038/nature13288

Experimental method

X-RAY DIFFRACTION (2.5 Å)