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TitleStructural insights into the binding modes of lanreotide and pasireotide with somatostatin receptor 1.
Journal, issue, pagesActa Pharm Sin B, Vol. 15, Issue 5, Page 2468-2479, Year 2025
Publish dateMar 20, 2025
AuthorsZicheng Zeng / Qiwen Liao / Shiyi Gan / Xinyu Li / Tiantian Xiong / Lezhi Xu / Dan Li / Yunlu Jiang / Jing Chen / Richard Ye / Yang Du / Thiansze Wong /
PubMed AbstractSomatostatin receptor 1 (SSTR1) is a crucial therapeutic target for various neuroendocrine and oncological disorders. Current SSTR1-targeted treatments, including the first-generation somatostatin ...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.
External linksActa Pharm Sin B / PubMed:40487642 / PubMed Central
MethodsEM (single particle)
Resolution2.82 - 3.37 Å
Structure data

60650

9ik8

EMDB-60650, PDB-9ik8:
Cryo-EM Structure of SSTR1-Gi SST analogs complex
Method: EM (single particle) / Resolution: 2.82 Å

60651

9ik9

EMDB-60651, PDB-9ik9:
Cryo-EM Structure of SST analogs bond SSTR1-Gi complex
Method: EM (single particle) / Resolution: 3.37 Å

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / SSTR1 / SST analogs

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