2. Academic Validation
  3. Cryo-EM structures of adenosine receptor A3AR bound to selective agonists

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

  • Nat Commun. 2024 Apr 16;15(1):3252. doi: 10.1038/s41467-024-47207-6.
Hongmin Cai # 1,  Shimeng Guo # 2,  Youwei Xu # 2,  Jun Sun # 2 3,  Junrui Li 2,  Zhikan Xia 2,  Yi Jiang 4,  Xin Xie 5 6 7 8 9,  H Eric Xu 10 11 12
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. caihongmin@simm.ac.cn.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 Lingang Laboratory, Shanghai, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. xxie@simm.ac.cn.
  • 6 University of Chinese Academy of Sciences, Beijing, China. xxie@simm.ac.cn.
  • 7 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. xxie@simm.ac.cn.
  • 8 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. xxie@simm.ac.cn.
  • 9 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research, Institute for Drug Discovery, Yantai, China. xxie@simm.ac.cn.
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
  • 11 University of Chinese Academy of Sciences, Beijing, China. eric.xu@simm.ac.cn.
  • 12 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. eric.xu@simm.ac.cn.
  • # Contributed equally.
PMID: 38627384 DOI: 10.1038/s41467-024-47207-6
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.

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