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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\u2019s 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.<\/jats:p>","DOI":"10.1073\/pnas.2522515122","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T17:27:48Z","timestamp":1766165268000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Structural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4932-0695","authenticated-orcid":false,"given":"Yang","family":"Li","sequence":"first","affiliation":[{"name":"Department of pharmacology, School of Pharmacy, Fudan University","place":["Shanghai, China"]},{"name":"State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2142-6230","authenticated-orcid":false,"given":"Zhongliang","family":"Xing","sequence":"additional","affiliation":[{"name":"Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6829-8144","authenticated-orcid":false,"given":"H. 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