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| | ==Crystal structure of P2Y12 receptor in complex with 2MeSADP== | | ==Crystal structure of P2Y12 receptor in complex with 2MeSADP== |
| - | <StructureSection load='4pxz' size='340' side='right' caption='[[4pxz]], [[Resolution|resolution]] 2.50Å' scene=''> | + | <StructureSection load='4pxz' size='340' side='right'caption='[[4pxz]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4pxz]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PXZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PXZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4pxz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PXZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PXZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6AD:2-(METHYLSULFANYL)ADENOSINE+5-(TRIHYDROGEN+DIPHOSPHATE)'>6AD</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6AD:2-(METHYLSULFANYL)ADENOSINE+5-(TRIHYDROGEN+DIPHOSPHATE)'>6AD</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ntj|4ntj]], [[4py0|4py0]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4pxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pxz OCA], [https://pdbe.org/4pxz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pxz RCSB], [https://www.ebi.ac.uk/pdbsum/4pxz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pxz ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HORK3, P2RY12, P2Y12, cybC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4pxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pxz OCA], [http://pdbe.org/4pxz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pxz RCSB], [http://www.ebi.ac.uk/pdbsum/4pxz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pxz ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/P2Y12_HUMAN P2Y12_HUMAN]] Resistance to clopidogrel in myocardial infarction, cerebrovascular accident, oblitering arteriopathy of the lower limbs;P2Y12 defect. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/P2Y12_HUMAN P2Y12_HUMAN] Resistance to clopidogrel in myocardial infarction, cerebrovascular accident, oblitering arteriopathy of the lower limbs;P2Y12 defect. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/P2Y12_HUMAN P2Y12_HUMAN]] Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Involved in platelet aggregation. | + | [https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function.[https://www.uniprot.org/uniprot/P2Y12_HUMAN P2Y12_HUMAN] Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Involved in platelet aggregation. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus coli migula 1895]] | + | [[Category: Escherichia coli]] |
| - | [[Category: Cherezov, V]] | + | [[Category: Homo sapiens]] |
| - | [[Category: GPCR, GPCR Network]] | + | [[Category: Large Structures]] |
| - | [[Category: Gao, Z G]] | + | [[Category: Cherezov V]] |
| - | [[Category: Han, G W]] | + | [[Category: Gao ZG]] |
| - | [[Category: Jacobson, K A]] | + | [[Category: Han GW]] |
| - | [[Category: Jiang, H]] | + | [[Category: Jacobson KA]] |
| - | [[Category: Katritch, V]] | + | [[Category: Jiang H]] |
| - | [[Category: Li, T]] | + | [[Category: Katritch V]] |
| - | [[Category: Ma, L]] | + | [[Category: Li T]] |
| - | [[Category: Muller, C E]] | + | [[Category: Ma L]] |
| - | [[Category: Paoletta, S]] | + | [[Category: Muller CE]] |
| - | [[Category: Stevens, R C]] | + | [[Category: Paoletta S]] |
| - | [[Category: Wu, B]] | + | [[Category: Stevens RC]] |
| - | [[Category: Yang, H]] | + | [[Category: Wu B]] |
| - | [[Category: Zhang, D]] | + | [[Category: Yang H]] |
| - | [[Category: Zhang, J]] | + | [[Category: Zhang D]] |
| - | [[Category: Zhang, K]] | + | [[Category: Zhang J]] |
| - | [[Category: Zhang, W]] | + | [[Category: Zhang K]] |
| - | [[Category: Zhao, Q]] | + | [[Category: Zhang W]] |
| - | [[Category: Agonist-bound]]
| + | [[Category: Zhao Q]] |
| - | [[Category: Gpcr]]
| + | |
| - | [[Category: Gpcr network]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Platelet activation]]
| + | |
| - | [[Category: Psi-biology]]
| + | |
| - | [[Category: Purinergic receptor p2y12]]
| + | |
| - | [[Category: Signaling membrane protein]]
| + | |
| - | [[Category: Signaling protein-agonist complex]]
| + | |
| - | [[Category: Structural genomic]]
| + | |
| Structural highlights
Disease
P2Y12_HUMAN Resistance to clopidogrel in myocardial infarction, cerebrovascular accident, oblitering arteriopathy of the lower limbs;P2Y12 defect. The disease is caused by mutations affecting the gene represented in this entry.
Function
C562_ECOLX Electron-transport protein of unknown function.P2Y12_HUMAN Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Involved in platelet aggregation.
Publication Abstract from PubMed
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 A resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5'-triphosphate (2MeSATP) at 3.1 A 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 delta-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.
Agonist-bound structure of the human P2Y12 receptor.,Zhang J, Zhang K, Gao ZG, Paoletta S, Zhang D, Han GW, Li T, Ma L, Zhang W, Muller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q Nature. 2014 May 1;509(7498):119-22. doi: 10.1038/nature13288. PMID:24784220[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang J, Zhang K, Gao ZG, Paoletta S, Zhang D, Han GW, Li T, Ma L, Zhang W, Muller CE, Yang H, Jiang H, Cherezov V, Katritch V, Jacobson KA, Stevens RC, Wu B, Zhao Q. Agonist-bound structure of the human P2Y12 receptor. Nature. 2014 May 1;509(7498):119-22. doi: 10.1038/nature13288. PMID:24784220 doi:http://dx.doi.org/10.1038/nature13288
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