8C9W

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

Summary for 8C9W

• Entry DOI: 10.2210/pdb8c9w/pdb
• Descriptor: 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)
• Functional Keywords: gpcr, bril, antagonist, purinergic signaling, cancer immunotherapy, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 52331.55

Authors

Strater, N.,Claff, T.,Schlegel, J.G.,Voss, J.H.,Vaassen, V.,Muller, C.E. (deposition date: 2023-01-23, release date: 2023-07-12, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.114 Å)