8jlz
ST1936-5HT6R complex
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 serotonin receptor 5-HT(6)R is an important G-protein-coupled receptor (GPCR) that involved in essential functions within the central and peripheral nervous systems and is linked to various psychiatric disorders. Selective activation of 5-HT(6)R promotes neural stem cell regeneration activity. As a 5-HT(6)R selective agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N, N-dimethylethanolamine (ST1936) has been widely used to investigate the functions of the 5-HT(6)R. The molecular mechanism of how ST1936 is recognized by 5-HT(6)R and how it effectively couples with Gs remain unclear. Here, we reconstituted the ST1936-5-HT(6)R-Gs complex in vitro and solved its cryo-electron microscopy structure at 3.1 A resolution. Further structural analysis and mutational studies facilitated us to identify the residues of the Y310(7.43) and "toggle switch" W281(6.48) of the 5-HT(6)R contributed to the higher efficacy of ST1936 compared with 5-HT. By uncovering the structural foundation of how 5-HT(6)R specifically recognizes agonists and elucidating the molecular process of G protein activation, our discoveries offer valuable insights and pave the way for the development of promising 5-HT(6)R agonists. Structural insight into the selective agonist ST1936 binding of serotonin receptor 5-HT6.,Pei Y, Wen X, Guo SC, Yang ZS, Zhang R, Xiao P, Sun JP Biochem Biophys Res Commun. 2023 Sep 3;671:327-334. doi: , 10.1016/j.bbrc.2023.05.126. Epub 2023 Jun 5. PMID:37327704[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
