8X17

Cryo-EM structure of adenosine receptor A3AR bound to CF102

Summary for 8X17

• Entry DOI: 10.2210/pdb8x17/pdb
• EMDB information: 37986
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Adenosine receptor A3, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, adenosine a3 receptor, ligand selectivity, cf102, membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 5
• Total formula weight: 149258.19

Authors

Cai, H.,Xu, Y.,Xu, H.E. (deposition date: 2023-11-06, release date: 2024-04-24, Last modification date: 2024-11-13)

Primary citation

Cai, H.,Guo, S.,Xu, Y.,Sun, J.,Li, J.,Xia, Z.,Jiang, Y.,Xie, X.,Xu, H.E.
Cryo-EM structures of adenosine receptor A 3 AR bound to selective agonists.
Nat Commun, 15:3252-3252, 2024

PubMed Abstract: The adenosine A receptor (AAR), a key member of the G protein-coupled receptor family, is a promising therapeutic target for inflammatory and cancerous conditions. The selective AAR 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 AAR bound to CF101 and CF102 with heterotrimeric G 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 AAR's ligand selectivity and receptor activation. Key mutations, including His, Ser, and Ser, in a unique sub-pocket of AAR, significantly impact receptor activation. Comparative analysis with the inactive AAR structure highlights a conserved receptor activation mechanism. Our findings provide comprehensive insights into the molecular recognition and signaling of AAR, paving the way for designing subtype-selective adenosine receptor ligands.

PubMed: 38627384
DOI: 10.1038/s41467-024-47207-6

Experimental method

ELECTRON MICROSCOPY (3.19 Å)