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- PDB-9w32: antagonist 1-bound inactive SSTR5 structure -

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Basic information

Entry
Database: PDB / ID: 9w32
Titleantagonist 1-bound inactive SSTR5 structure
ComponentsSomatostatin receptor type 5,Soluble cytochrome b562
KeywordsSTRUCTURAL PROTEIN / GPCR / antagonist / inactive structure / SSTR5
Function / homology
Function and homology information


somatostatin receptor activity / neuropeptide binding / cellular response to glucocorticoid stimulus / positive regulation of cytokinesis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / regulation of insulin secretion / Peptide ligand-binding receptors / electron transport chain / glucose homeostasis ...somatostatin receptor activity / neuropeptide binding / cellular response to glucocorticoid stimulus / positive regulation of cytokinesis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / regulation of insulin secretion / Peptide ligand-binding receptors / electron transport chain / glucose homeostasis / G alpha (i) signalling events / electron transfer activity / periplasmic space / neuron projection / iron ion binding / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / heme binding / plasma membrane
Similarity search - Function
Somatostatin receptor 5 / Somatostatin receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
: / Soluble cytochrome b562 / Somatostatin receptor type 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsLi, Y. / Xing, Z. / Zhao, L. / Xu, H.E.
Funding support China, 4items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371255 China
National Natural Science Foundation of China (NSFC)32071203 China
National Natural Science Foundation of China (NSFC)32130022 China
National Natural Science Foundation of China (NSFC)82121005 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Structural insights into nonpeptide antagonist inhibition of somatostatin receptor subtype 5.
Authors: Yang Li / Zhongliang Xing / Wen Hu / Kai Wu / H Eric Xu / Li-Hua Zhao /
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 ...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.
History
DepositionJul 28, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Somatostatin receptor type 5,Soluble cytochrome b562
B: Somatostatin receptor type 5,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,3834
Polymers85,3602
Non-polymers1,0232
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Somatostatin receptor type 5,Soluble cytochrome b562 / SS-5-R / SS5-R / SS5R / SST5 / Cytochrome b-562


Mass: 42680.105 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: SSTR5, cybC / Plasmid: pFast / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P35346, UniProt: P0ABE7
#2: Chemical ChemComp-A1EVP / 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 / SSTR5 antagonist 1


Mass: 511.585 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H34FN3O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: SSTR5 antagonist 1 / Type: COMPLEX / Details: small molecule, antagonist / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.18 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Escherichia coli (E. coli)562
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenConc.: 13.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: 13.1 mg/ml of the protein in a liquid buffer
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4619

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6.2particle selection
4cryoSPARC4.6.2CTF correction
7UCSF ChimeraX1.7.1model fitting
9cryoSPARC4.6.2initial Euler assignment
10cryoSPARC4.6.2final Euler assignment
11cryoSPARC4.6.2classification
12cryoSPARC4.6.23D reconstruction
13PHENIX1.9model refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 2700519
3D reconstructionResolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 128653 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model buildingDetails: AlphaFold3 predicted / Source name: AlphaFold / Type: in silico model

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