8cu7: Difference between revisions
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==Crystal structure of A2AAR-StaR2-bRIL in complex with a novel A2a antagonist, LJ-4517== | ==Crystal structure of A2AAR-StaR2-bRIL in complex with a novel A2a antagonist, LJ-4517== | ||
<StructureSection load='8cu7' size='340' side='right'caption='[[8cu7]]' scene=''> | <StructureSection load='8cu7' size='340' side='right'caption='[[8cu7]], [[Resolution|resolution]] 2.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8CU7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CU7 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8cu7]] 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=8CU7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CU7 FirstGlance]. <br> | ||
</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=8cu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cu7 OCA], [https://pdbe.org/8cu7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cu7 RCSB], [https://www.ebi.ac.uk/pdbsum/8cu7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cu7 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=ETF:TRIFLUOROETHANOL'>ETF</scene>, <scene name='pdbligand=LJX:(2~{R},3~{R},4~{R})-2-(6-azanyl-2-hex-1-ynyl-8-thiophen-2-yl-purin-9-yl)oxolane-3,4-diol'>LJX</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8cu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cu7 OCA], [https://pdbe.org/8cu7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cu7 RCSB], [https://www.ebi.ac.uk/pdbsum/8cu7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cu7 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/AA2AR_HUMAN AA2AR_HUMAN] Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.[https://www.uniprot.org/uniprot/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown function. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Modulators of the G protein-coupled A(2A) adenosine receptor (A(2A)AR) have been considered promising agents to treat Parkinson's disease, inflammation, cancer, and central nervous system disorders. Herein, we demonstrate that a thiophene modification at the C8 position in the common adenine scaffold converted an A(2A)AR agonist into an antagonist. We synthesized and characterized a novel A(2A)AR antagonist, 2 (LJ-4517), with K(i) = 18.3 nM. X-ray crystallographic structures of 2 in complex with two thermostabilized A(2A)AR constructs were solved at 2.05 and 2.80 A resolutions. In contrast to A(2A)AR agonists, which simultaneously interact with both Ser277(7.42) and His278(7.43), 2 only transiently contacts His278(7.43), which can be direct or water-mediated. The n-hexynyl group of 2 extends into an A(2A)AR exosite. Structural analysis revealed that the introduced thiophene modification restricted receptor conformational rearrangements required for subsequent activation. This approach can expand the repertoire of adenosine receptor antagonists that can be designed based on available agonist scaffolds. | |||
GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A(2A) Adenosine Receptor.,Shiriaeva A, Park D, Kim G, Lee Y, Hou X, Jarhad DB, Kim G, Yu J, Hyun YE, Kim W, Gao ZG, Jacobson KA, Han GW, Stevens RC, Jeong LS, Choi S, Cherezov V J Med Chem. 2022 Sep 8;65(17):11648-11657. doi: 10.1021/acs.jmedchem.2c00462. , Epub 2022 Aug 17. PMID:35977382<ref>PMID:35977382</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 8cu7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Escherichia coli]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Cherezov V]] | [[Category: Cherezov V]] | ||
Latest revision as of 14:51, 30 October 2024
Crystal structure of A2AAR-StaR2-bRIL in complex with a novel A2a antagonist, LJ-4517Crystal structure of A2AAR-StaR2-bRIL in complex with a novel A2a antagonist, LJ-4517
Structural highlights
FunctionAA2AR_HUMAN Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.C562_ECOLX Electron-transport protein of unknown function. Publication Abstract from PubMedModulators of the G protein-coupled A(2A) adenosine receptor (A(2A)AR) have been considered promising agents to treat Parkinson's disease, inflammation, cancer, and central nervous system disorders. Herein, we demonstrate that a thiophene modification at the C8 position in the common adenine scaffold converted an A(2A)AR agonist into an antagonist. We synthesized and characterized a novel A(2A)AR antagonist, 2 (LJ-4517), with K(i) = 18.3 nM. X-ray crystallographic structures of 2 in complex with two thermostabilized A(2A)AR constructs were solved at 2.05 and 2.80 A resolutions. In contrast to A(2A)AR agonists, which simultaneously interact with both Ser277(7.42) and His278(7.43), 2 only transiently contacts His278(7.43), which can be direct or water-mediated. The n-hexynyl group of 2 extends into an A(2A)AR exosite. Structural analysis revealed that the introduced thiophene modification restricted receptor conformational rearrangements required for subsequent activation. This approach can expand the repertoire of adenosine receptor antagonists that can be designed based on available agonist scaffolds. GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A(2A) Adenosine Receptor.,Shiriaeva A, Park D, Kim G, Lee Y, Hou X, Jarhad DB, Kim G, Yu J, Hyun YE, Kim W, Gao ZG, Jacobson KA, Han GW, Stevens RC, Jeong LS, Choi S, Cherezov V J Med Chem. 2022 Sep 8;65(17):11648-11657. doi: 10.1021/acs.jmedchem.2c00462. , Epub 2022 Aug 17. PMID:35977382[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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