8c9w

Crystal structure of the adenosine A2A receptor (construct A2A-PSB2-bRIL) complexed with Etrumadenant at the orthosteric pocket

spinqualitylabelsall models 8c9w, resolution 2.11Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8c9w is a 1 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.114Å Ligands: CLR, OLA, OLB, OLC, PEG, U30 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 PubMed The G(s) protein-coupled adenosine A(2A) receptor (A(2A)AR) represents an emerging drug target for cancer immunotherapy. The clinical candidate Etrumadenant was developed as an A(2A)AR antagonist with ancillary blockade of the A(2B)AR subtype. It constitutes a unique chemotype featuring a poly-substituted 2-amino-4-phenyl-6-triazolylpyrimidine core structure. Herein, we report two crystal structures of the A(2A)AR in complex with Etrumadenant, obtained with differently thermostabilized A(2A)AR constructs. This led to the discovery of an unprecedented interaction, a hydrogen bond of T88(3.36) with the cyano group of Etrumadenant. T88(3.36) is mutated in most A(2A)AR constructs used for crystallization, which has prevented the discovery of its interactions. In-vitro characterization of Etrumadenant indicated low selectivity versus the A(1)AR subtype, which can be rationalized by the structural data. These results will facilitate the future design of AR antagonists with desired selectivity. Moreover, they highlight the advantages of the employed A(2A)AR crystallization construct that is devoid of ligand binding site mutations. Crystal structure of adenosine A(2A) receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction.,Claff T, Schlegel JG, Voss JH, Vaassen VJ, Weisse RH, Cheng RKY, Markovic-Mueller S, Bucher D, Strater N, Muller CE Commun Chem. 2023 Jun 1;6(1):106. doi: 10.1038/s42004-023-00894-6. PMID:37264098 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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