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Title | Cryo-EM structures of adenosine receptor AAR bound to selective agonists. |
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Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 3252, Year 2024 |
Publish date | Apr 16, 2024 |
Authors | Hongmin Cai / Shimeng Guo / Youwei Xu / Jun Sun / Junrui Li / Zhikan Xia / Yi Jiang / Xin Xie / H Eric Xu / |
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 ...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. |
External links | Nat Commun / PubMed:38627384 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.19 - 3.29 Å |
Structure data | EMDB-37985, PDB-8x16: EMDB-37986, PDB-8x17: |
Chemicals | ChemComp-Q8L:
ChemComp-XS0: |
Source |
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Keywords | MEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / adenosine A3 receptor / ligand selectivity / CF101 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex / CF102 |