Somatostatin receptor 1(SSTR1)is a crucial therapeutic target for various neuroendocrine and oncological disorders.Current SSTR1-targeted treatments,including the first-generation somatostatin analog lanreotide(Lan)an...Somatostatin receptor 1(SSTR1)is a crucial therapeutic target for various neuroendocrine and oncological disorders.Current SSTR1-targeted treatments,including the first-generation somatostatin analog lanreotide(Lan)and the second-generation analog pasireotide(Pas),show promise but encounter challenges related to selectivity and efficacy.This study presents high-resolution cryo-electron microscopy structures of SSTR1 complexed with Lan or Pas,revealing the distinct mechanisms of ligand-binding and activation.These structures illustrate unique conformational changes in the SSTR1 orthosteric pocket induced by each ligand,which are critical for receptor activation and ligand selectivity.Combined with the biochemical assays and molecular dynamics simulations,our results provide a comparative analysis of binding characteristics within the SSTR family,highlighting subtle differences in SSTR1 activation by Lan and Pas.These insights pave the way for designing next-generation therapies with enhanced efficacy and reduced side effects through improved receptor subtype selectivity.展开更多
基金supported by funds from the Ganghong Young Scholar Development Fund(China)and the Shenzhen-Hong Kong Cooperation Zone for Technology and Innovation(No.HZQB-KCZYB-2020056,China)Thiansze Wong is supported by research fundings from Shenzhen Pengcheng Peacock Plan(Nos.2021TC0059 and 2024TC0153,China)+7 种基金Yang Du is supported by grants from the National Natural Science Foundation of China(No.32271263)Shenzhen Sci.&Tech Innovation Bureau(Nos.JCYJ 20220818103009018 and JCYJ 20240813113521028,China)and the Shenzhen-Hong Kong Cooperation Zone for Technology and Innovation(No.HZQB-KCZYB-2020056,China)Richard Ye is supported by Shenzhen Medical Research Fund(No.SMRFD2403009,China)Joint Research Fund of the Second Affiliated Hospital-School of Medicine,the Chinese University of Hong Kong,Shenzhen(No.YXLH13,China)Ganghong Young Scholar Development Fund(No.2019E0020)and Fund from Shenzhen-Hong Kong Cooperation Zone for Technology and Innovation(No.HZQB-KCZYB-2020056,China)Jing Chen is supported by the National Natural Science Foundation of China(No.31271243)。
文摘Somatostatin receptor 1(SSTR1)is a crucial therapeutic target for various neuroendocrine and oncological disorders.Current SSTR1-targeted treatments,including the first-generation somatostatin analog lanreotide(Lan)and the second-generation analog pasireotide(Pas),show promise but encounter challenges related to selectivity and efficacy.This study presents high-resolution cryo-electron microscopy structures of SSTR1 complexed with Lan or Pas,revealing the distinct mechanisms of ligand-binding and activation.These structures illustrate unique conformational changes in the SSTR1 orthosteric pocket induced by each ligand,which are critical for receptor activation and ligand selectivity.Combined with the biochemical assays and molecular dynamics simulations,our results provide a comparative analysis of binding characteristics within the SSTR family,highlighting subtle differences in SSTR1 activation by Lan and Pas.These insights pave the way for designing next-generation therapies with enhanced efficacy and reduced side effects through improved receptor subtype selectivity.
