Cryo-EM structures of adenosine receptor A3AR bound to selective agonists

Hongmin Cai (), Shimeng Guo, Youwei Xu, Jun Sun, Junrui Li, Zhikan Xia, Yi Jiang, Xin Xie () and H. Eric Xu ()
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Hongmin Cai: Chinese Academy of Sciences
Shimeng Guo: Chinese Academy of Sciences
Youwei Xu: Chinese Academy of Sciences
Jun Sun: Chinese Academy of Sciences
Junrui Li: Chinese Academy of Sciences
Zhikan Xia: Chinese Academy of Sciences
Yi Jiang: Lingang Laboratory
Xin Xie: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract The adenosine A3 receptor (A3AR), a key member of the G protein-coupled receptor family, is a promising therapeutic target for inflammatory and cancerous conditions. The selective A3AR agonists, CF101 and CF102, are clinically significant, yet their recognition mechanisms remained elusive. Here we report the cryogenic electron microscopy structures of the full-length human A3AR bound to CF101 and CF102 with heterotrimeric Gi protein in complex at 3.3-3.2 Å resolution. These agonists reside in the orthosteric pocket, forming conserved interactions via their adenine moieties, while their 3-iodobenzyl groups exhibit distinct orientations. Functional assays reveal the critical role of extracellular loop 3 in A3AR’s ligand selectivity and receptor activation. Key mutations, including His3.37, Ser5.42, and Ser6.52, in a unique sub-pocket of A3AR, significantly impact receptor activation. Comparative analysis with the inactive A2AAR structure highlights a conserved receptor activation mechanism. Our findings provide comprehensive insights into the molecular recognition and signaling of A3AR, paving the way for designing subtype-selective adenosine receptor ligands.

Date: 2024
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DOI: 10.1038/s41467-024-47207-6

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