9W32

antagonist 1-bound inactive SSTR5 structure

This is a non-PDB format compatible entry.

Summary for 9W32

• Entry DOI: 10.2210/pdb9w32/pdb
• EMDB information: 65588 65589
• Descriptor: Somatostatin receptor type 5,Soluble cytochrome b562, 1-[2-[[3,5-diethoxy-4-(4-fluorophenyl)phenyl]methyl]-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl]piperidine-4-carboxylic acid (2 entities in total)
• Functional Keywords: gpcr, antagonist, inactive structure, sstr5, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 86383.38

Authors

Li, Y.,Xing, Z.,Zhao, L.,Xu, H.E. (deposition date: 2025-07-28, release date: 2026-01-21)

Primary citation

Li, Y.,Xing, Z.,Hu, W.,Wu, K.,Xu, H.E.,Zhao, L.H.
Structural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5.
Proc.Natl.Acad.Sci.USA, 122:e2522515122-e2522515122, 2025

PubMed Abstract: 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.

PubMed: 41417603
DOI: 10.1073/pnas.2522515122

Experimental method

ELECTRON MICROSCOPY (2.59 Å)