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TitleStructural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 51, Page e2522515122, Year 2025
Publish dateDec 23, 2025
AuthorsYang Li / Zhongliang Xing / Wen Hu / Kai Wu / H Eric Xu / Li-Hua Zhao /
PubMed AbstractThe somatostatin receptor subtype 5 (SSTR5) is a critical pharmacological target involved in neuroendocrine signaling, metabolic regulation, and tumorigenesis. Despite its therapeutic potential, the ...The somatostatin receptor subtype 5 (SSTR5) is a critical pharmacological target involved in neuroendocrine signaling, metabolic regulation, and tumorigenesis. Despite its therapeutic potential, the structural mechanisms underlying SSTR5 inhibition by nonpeptide antagonists remain largely unresolved. In this study, we present high-resolution cryoelectron microscopy structures of human SSTR5 in complex with two selective small-molecule antagonists, antagonist 1 and S5A1, revealing the receptor's inactive conformation. Both antagonists induce a unique remodeling of extracellular loop 2, which adopts a capping architecture that sterically occludes the orthosteric site, thus preventing agonist access and stabilizing receptor inactivation. Structural analyses and functional experiments elucidate how distinct molecular moieties of the antagonists differentially contribute to inhibitory efficacy, and subtype selectivity. Furthermore, we delineate rational avenues for molecular optimization to enhance therapeutic index and mitigate off-target liabilities. These findings, complementing our previous agonist-bound structures, establish a comprehensive structural foundation for developing improved nonpeptidic SSTR5 antagonists with potential therapeutic applications for type 2 diabetes and related endocrine disorders.
External linksProc Natl Acad Sci U S A / PubMed:41417603 / PubMed Central
MethodsEM (single particle)
Resolution2.59 - 2.69 Å
Structure data

65588

9w32

EMDB-65588, PDB-9w32:
antagonist 1-bound inactive SSTR5 structure
Method: EM (single particle) / Resolution: 2.59 Å

65589

9w33

EMDB-65589, PDB-9w33:
S5A1-bound inactive SSTR5 structure
Method: EM (single particle) / Resolution: 2.69 Å

Chemicals

PDB-1evp:
CRYSTAL STRUCTURE OF THE CHIMERICAL DECAMER D(CCACTAGTG)R(G)

PDB-1evq:
THE CRYSTAL STRUCTURE OF THE THERMOPHILIC CARBOXYLESTERASE EST2 FROM ALICYCLOBACILLUS ACIDOCALDARIUS

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsSTRUCTURAL PROTEIN / GPCR / antagonist / inactive structure / SSTR5

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