7xy7
Adenosine receptor bound to a non-selective agonist in complex with a G protein obtained by cryo-EM
Structural highlights
DiseaseGNAS2_HUMAN Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGNAS2_HUMAN Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).[1] [2] [3] [4] [5] Publication Abstract from PubMedThe human adenosine A(2B) receptor (A(2B)R) is a class A G protein-coupled receptor that is involved in several major physiological and pathological processes throughout the body. A(2B)R recognizes its ligands adenosine and NECA with relatively low affinity, but the detailed mechanism for its ligand recognition and signaling is still elusive. Here, we present two structures determined by cryo-electron microscopy of A(2B)R bound to its agonists NECA and BAY60-6583, each coupled to an engineered G(s) protein. The structures reveal conserved orthosteric binding pockets with subtle differences, whereas the selectivity or specificity can mainly be attributed to regions extended from the orthosteric pocket. We also found that BAY60-6583 occupies a secondary pocket, where residues V250(6.51) and N273(7.36) were two key determinants for its selectivity against A(2B)R. This study offers a better understanding of ligand selectivity for the adenosine receptor family and provides a structural template for further development of A(2B)R ligands for related diseases. Cryo-EM structure of the human adenosine A(2B) receptor-G(s) signaling complex.,Chen Y, Zhang J, Weng Y, Xu Y, Lu W, Liu W, Liu M, Hua T, Song G Sci Adv. 2022 Dec 23;8(51):eadd3709. doi: 10.1126/sciadv.add3709. Epub 2022 Dec , 23. PMID:36563137[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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