7y27
Cryo-EM structure of the SST-14-bound SSTR2-miniGq-scFv16 complexCryo-EM structure of the SST-14-bound SSTR2-miniGq-scFv16 complex
Structural highlights
FunctionSSR2_HUMAN Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization.[1] [2] [3] [4] [5] Publication Abstract from PubMedG protein-coupled receptors (GPCRs) modulate every aspect of physiological functions mainly through activating heterotrimeric G proteins. A majority of GPCRs promiscuously couple to multiple G protein subtypes. Here we validate that in addition to the well-known G(i/o) pathway, somatostatin receptor 2 and 5 (SSTR2 and SSTR5) couple to the G(q/11) pathway and show that smaller ligands preferentially activate the G(i/o) pathway. We further determined cryo-electron microscopy structures of the SSTR2âG(o) and SSTR2âG(q) complexes bound to octreotide and SST-14. Structural and functional analysis revealed that G protein selectivity of SSTRs is not only determined by structural elements in the receptor-G protein interface, but also by the conformation of the agonist-binding pocket. Accordingly, smaller ligands fail to stabilize a broader agonist-binding pocket of SSTRs that is required for efficient G(q/11) coupling but not G(i/o) coupling. Our studies facilitate the design of drugs with selective G protein signaling to improve therapeutic efficacy. Molecular basis for the selective G protein signaling of somatostatin receptors.,Chen S, Teng X, Zheng S Nat Chem Biol. 2023 Feb;19(2):133-140. doi: 10.1038/s41589-022-01130-3. Epub 2022 , Sep 22. PMID:36138141[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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