8jwz

Crystal structure of A2AR-T4L in complex with AB928

spinqualitylabelsall models 8jwz, resolution 2.37Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8jwz is a 1 chain structure with sequence from Escherichia virus T4 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 2.37Å Ligands: CLR, NA, OLA, 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.D9IEF7_BPT4 Publication Abstract from PubMed The adenosine subfamily G protein-coupled receptors A(2A)R and A(2B)R have been identified as promising cancer immunotherapy candidates. One of the A(2A)R/A(2B)R dual antagonists, AB928, has progressed to a phase II clinical trial to treat rectal cancer. However, the precise mechanism underlying its dual-antagonistic properties remains elusive. Herein, we report crystal structures of the A(2A)R complexed with AB928 and a selective A(2A)R antagonist 2-118. The structures revealed a common binding mode on A(2A)R, wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets. In contrast, the cAMP assay and A(2A)R and A(2B)R molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A(2B)R. Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A(2B)R pocket, while 2-118 did not due to intrinsic differences. This disparity potentially accounted for the difference in inhibitory efficacy between A(2B)R and A(2A)R. This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A(2A)R/A(2B)R for cancer therapy. Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A(2) receptors.,Weng Y, Yang X, Zhang Q, Chen Y, Xu Y, Zhu C, Xie Q, Wang Y, Yang H, Liu M, Lu W, Song G Sci China Life Sci. 2024 May;67(5):986-995. doi: 10.1007/s11427-023-2459-8. Epub , 2024 Jan 31. PMID:38319473 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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