8x17
Cryo-EM structure of adenosine receptor A3AR bound to CF102
Structural highlights
FunctionGNAI1_BOVIN Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (By similarity). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (By similarity). The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. Required for normal cytokinesis during mitosis (By similarity). Required for cortical dynein-dynactin complex recruitment during metaphase (By similarity).[UniProtKB:P10824][UniProtKB:P63096] Publication Abstract from PubMedThe adenosine A(3) receptor (A(3)AR), a key member of the G protein-coupled receptor family, is a promising therapeutic target for inflammatory and cancerous conditions. The selective A(3)AR 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 A(3)AR bound to CF101 and CF102 with heterotrimeric G(i) protein in complex at 3.3-3.2 A 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 A(3)AR's ligand selectivity and receptor activation. Key mutations, including His(3.37), Ser(5.42), and Ser(6.52), in a unique sub-pocket of A(3)AR, significantly impact receptor activation. Comparative analysis with the inactive A(2A)AR structure highlights a conserved receptor activation mechanism. Our findings provide comprehensive insights into the molecular recognition and signaling of A(3)AR, paving the way for designing subtype-selective adenosine receptor ligands. Cryo-EM structures of adenosine receptor A(3)AR bound to selective agonists.,Cai H, Guo S, Xu Y, Sun J, Li J, Xia Z, Jiang Y, Xie X, Xu HE Nat Commun. 2024 Apr 16;15(1):3252. doi: 10.1038/s41467-024-47207-6. PMID:38627384[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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