7xau | pdb_00007xau
Structure of somatostatin receptor 2 bound with octreotide.
Structural highlights
Function[SSR2_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 PubMedThe endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1-5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short cyclic SST analogues (lanreotide or octreotide) with improved stability and longer lifetime were developed as drugs to preferentially activate SSTR2 and treat acromegalia and neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2-Gi complex bound with SST14, octreotide or lanreotide were determined at resolutions of 2.85 A, 2.97 A, and 2.87 A, respectively. Structural and functional analysis revealed that interactions between beta-turn residues in SST analogues and transmembrane SSTR2 residues in the ligand-binding pocket are crucial for receptor binding and functional stimulation of the two SST14-derived cyclic octapeptides. Additionally, Q102(2.63), N276(6.55), and F294(7.35) could be responsible for the selectivity of lanreotide or octreotide for SSTR2 over SSTR1 or SSTR4. These results provide valuable insights into further rational development of SST analogue drugs targeting SSTR2. Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues.,Bo Q, Yang F, Li Y, Meng X, Zhang H, Zhou Y, Ling S, Sun D, Lv P, Liu L, Shi P, Tian C Cell Discov. 2022 May 20;8(1):47. doi: 10.1038/s41421-022-00405-2. PMID:35595746[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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