8cu7
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
Function[AA2AR_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 A2A adenosine receptor (A2AAR) 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 A2AAR agonist into an antagonist. We synthesized and characterized a novel A2AAR antagonist, 2 (LJ-4517), with Ki = 18.3 nM. X-ray crystallographic structures of 2 in complex with two thermostabilized A2AAR constructs were solved at 2.05 and 2.80 A resolutions. In contrast to A2AAR 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 A2AAR 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 A2A 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 Aug 17. doi: 10.1021/acs.jmedchem.2c00462. PMID:35977382[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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