8C9W

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

8C9W の概要

• エントリーDOI: 10.2210/pdb8c9w/pdb
• 分子名称: Adenosine receptor A2a,Soluble cytochrome b562, 3-[2-azanyl-6-[1-[[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]methyl]-1,2,3-triazol-4-yl]pyrimidin-4-yl]-2-methyl-benzenecarbonitrile, CHOLESTEROL, ... (8 entities in total)
• 機能のキーワード: gpcr, bril, antagonist, purinergic signaling, cancer immunotherapy, membrane 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: 52331.55

構造登録者

Strater, N.,Claff, T.,Schlegel, J.G.,Voss, J.H.,Vaassen, V.,Muller, C.E. (登録日: 2023-01-23, 公開日: 2023-07-12, 最終更新日: 2024-11-06)

主引用文献

Claff, T.,Schlegel, J.G.,Voss, J.H.,Vaassen, V.J.,Weisse, R.H.,Cheng, R.K.Y.,Markovic-Mueller, S.,Bucher, D.,Strater, N.,Muller, C.E.
Crystal structure of adenosine A 2A receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction.
Commun Chem, 6:106-106, 2023

PubMed Abstract: The G protein-coupled adenosine A receptor (AAR) represents an emerging drug target for cancer immunotherapy. The clinical candidate Etrumadenant was developed as an AAR antagonist with ancillary blockade of the AAR 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 AAR in complex with Etrumadenant, obtained with differently thermostabilized AAR constructs. This led to the discovery of an unprecedented interaction, a hydrogen bond of T88 with the cyano group of Etrumadenant. T88 is mutated in most AAR constructs used for crystallization, which has prevented the discovery of its interactions. In-vitro characterization of Etrumadenant indicated low selectivity versus the AAR 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 AAR crystallization construct that is devoid of ligand binding site mutations.

PubMed: 37264098
DOI: 10.1038/s42004-023-00894-6

実験手法

X-RAY DIFFRACTION (2.114 Å)