8JWY

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

8JWY の概要

• エントリーDOI: 10.2210/pdb8jwy/pdb
• 分子名称: 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)
• 機能のキーワード: adenosine receptor 2a, gpcr, inhibitor, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 60361.95

構造登録者

Weng, Y.,Chen, Y.,Xu, Y.,Song, G. (登録日: 2023-06-29, 公開日: 2023-08-16, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.33 Å)