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Cryo-EM structures of adenosine receptor A3AR bound to selective agonists.
Cai, Hongmin; Guo, Shimeng; Xu, Youwei; Sun, Jun; Li, Junrui; Xia, Zhikan; Jiang, Yi; Xie, Xin; Xu, H Eric.
Affiliation
  • Cai H; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. caihongmin@simm.ac.cn.
  • Guo S; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Xu Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Sun J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Li J; University of Chinese Academy of Sciences, Beijing, China.
  • Xia Z; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Jiang Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Xie X; Lingang Laboratory, Shanghai, China.
  • Xu HE; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. xxie@simm.ac.cn.
Nat Commun ; 15(1): 3252, 2024 Apr 16.
Article in En | MEDLINE | ID: mdl-38627384
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Receptor, Adenosine A3 Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Receptor, Adenosine A3 Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country:
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