8JWY

Crystal structure of A2AR-T4L in complex with 2-118

Summary for 8JWY

• Entry DOI: 10.2210/pdb8jwy/pdb
• Descriptor: Adenosine receptor A2a,Endolysin, 3-[2-azanyl-6-[2-oxidanylidene-1-[[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]methyl]pyridin-4-yl]pyrimidin-4-yl]-2-methyl-benzenecarbonitrile, CHOLESTEROL, ... (7 entities in total)
• Functional Keywords: adenosine receptor 2a, gpcr, inhibitor, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 60361.95

Authors

Weng, Y.,Chen, Y.,Xu, Y.,Song, G. (deposition date: 2023-06-29, release date: 2023-08-16, Last modification date: 2024-10-23)

Primary citation

Weng, Y.,Yang, X.,Zhang, Q.,Chen, Y.,Xu, Y.,Zhu, C.,Xie, Q.,Wang, Y.,Yang, H.,Liu, M.,Lu, W.,Song, G.
Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A 2 receptors.
Sci China Life Sci, 67:986-995, 2024

PubMed Abstract: The adenosine subfamily G protein-coupled receptors AR and AR have been identified as promising cancer immunotherapy candidates. One of the AR/AR 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 AR complexed with AB928 and a selective AR antagonist 2-118. The structures revealed a common binding mode on AR, wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets. In contrast, the cAMP assay and AR and AR molecular dynamics simulations indicated that the ligands adopted distinct binding modes on AR. Detailed analysis of their chemical structures suggested that AB928 readily adapted to the AR pocket, while 2-118 did not due to intrinsic differences. This disparity potentially accounted for the difference in inhibitory efficacy between AR and AR. This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting AR/AR for cancer therapy.

PubMed: 38319473
DOI: 10.1007/s11427-023-2459-8

Experimental method

X-RAY DIFFRACTION (2.33 Å)