9w32

antagonist 1-bound inactive SSTR5 structure

spinqualitylabelsall models 9w32, resolution 2.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9w32 is a 2 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.59Å Ligands: A1EVP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function C562_ECOLX Electron-transport protein of unknown function.SSR5_HUMAN Receptor for somatostatin 28 and to a lesser extent for somatostatin-14. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. Increases cell growth inhibition activity of SSTR2 following heterodimerization. Publication Abstract from PubMed 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. Structural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5.,Li Y, Xing Z, Hu W, Wu K, Xu HE, Zhao LH Proc Natl Acad Sci U S A. 2025 Dec 23;122(51):e2522515122. doi: , 10.1073/pnas.2522515122. Epub 2025 Dec 19. PMID:41417603 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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