8CU7
Crystal structure of A2AAR-StaR2-bRIL in complex with a novel A2a antagonist, LJ-4517
Summary for 8CU7
| Entry DOI | 10.2210/pdb8cu7/pdb |
| Descriptor | Adenosine receptor A2a,Soluble cytochrome b562, DI(HYDROXYETHYL)ETHER, (2R,3R,4R)-2-[(8P)-6-amino-2-(hex-1-yn-1-yl)-8-(thiophen-2-yl)-9H-purin-9-yl]oxolane-3,4-diol, ... (9 entities in total) |
| Functional Keywords | gpcr, a2a adenosine receptor, lcp, s277a mutant, nucleoside, antagonist, molecular dynamics, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 60770.21 |
| Authors | Shiriaeva, A.,Park, D.-J.,Kim, G.,Lee, Y.,Hou, X.,Jarhad, D.B.,Kim, G.,Yu, J.,Hyun, Y.E.,Kim, W.,Gao, Z.-G.,Jacobson, K.A.,Han, G.W.,Stevens, R.C.,Jeong, L.S.,Choi, S.,Cherezov, V. (deposition date: 2022-05-16, release date: 2022-08-31, Last modification date: 2024-10-30) |
| Primary citation | Shiriaeva, A.,Park, D.,Kim, G.,Lee, Y.,Hou, X.,Jarhad, D.B.,Kim, G.,Yu, J.,Hyun, Y.E.,Kim, W.,Gao, Z.G.,Jacobson, K.A.,Han, G.W.,Stevens, R.C.,Jeong, L.S.,Choi, S.,Cherezov, V. GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A 2A Adenosine Receptor. J.Med.Chem., 65:11648-11657, 2022 Cited by PubMed Abstract: Modulators of the G protein-coupled A adenosine receptor (AAR) 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 AAR agonist into an antagonist. We synthesized and characterized a novel AAR antagonist, (LJ-4517), with = 18.3 nM. X-ray crystallographic structures of in complex with two thermostabilized AAR constructs were solved at 2.05 and 2.80 Å resolutions. In contrast to AAR agonists, which simultaneously interact with both Ser277 and His278, only transiently contacts His278, which can be direct or water-mediated. The -hexynyl group of extends into an AAR 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. PubMed: 35977382DOI: 10.1021/acs.jmedchem.2c00462 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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