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- EMDB-65588: antagonist 1-bound inactive SSTR5 structure -

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Basic information

Entry
Database: EMDB / ID: EMD-65588
Titleantagonist 1-bound inactive SSTR5 structure
Map data
Sample
  • Complex: SSTR5 antagonist 1
    • Protein or peptide: Somatostatin receptor type 5,Soluble cytochrome b562
  • Ligand: 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
KeywordsGPCR / antagonist / inactive structure / SSTR5 / STRUCTURAL PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsLi Y / Xing Z / Zhao L / Xu HE
Funding support China, 4 items
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, 2025-
Header (metadata) releaseJan 21, 2026-
Map releaseJan 21, 2026-
UpdateJan 21, 2026-
Current statusJan 21, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_65588.png

Downloads & links

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Map

FileDownload / File: emd_65588.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 400 pix.
= 292. Å		0.73 Å/pix.
x 400 pix.
= 292. Å		0.73 Å/pix.
x 400 pix.
= 292. Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.252
Minimum - Maximum-0.83521426 - 1.387971
Average (Standard dev.)-0.0016929201 (±0.02847215)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 292.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_65588_additional_1.map
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Half map: #1

Fileemd_65588_half_map_1.map
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Half map: #2

Fileemd_65588_half_map_2.map
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Sample components

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Entire : SSTR5 antagonist 1

EntireName: SSTR5 antagonist 1
Components
  • Complex: SSTR5 antagonist 1
    • Protein or peptide: Somatostatin receptor type 5,Soluble cytochrome b562
  • Ligand: 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

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Supramolecule #1: SSTR5 antagonist 1

SupramoleculeName: SSTR5 antagonist 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: small molecule, antagonist
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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Macromolecule #1: Somatostatin receptor type 5,Soluble cytochrome b562

MacromoleculeName: Somatostatin receptor type 5,Soluble cytochrome b562 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.680105 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: SAGARAVLVP VLYLLVCAAG LGGNTLVIYV VLRFAKMKTV TNIYILNLAV ADVLYMLGLP FLATQNAASF WPFGPVLCRL VMTLDGVNQ FTSVFCLTVM SVDRYLAVVH PLSSARWRRP RVAKLASAAA WVLSLCMSLP LLVFADVQEG GTCNASWPEP V GLWGAVFI ...String:
SAGARAVLVP VLYLLVCAAG LGGNTLVIYV VLRFAKMKTV TNIYILNLAV ADVLYMLGLP FLATQNAASF WPFGPVLCRL VMTLDGVNQ FTSVFCLTVM SVDRYLAVVH PLSSARWRRP RVAKLASAAA WVLSLCMSLP LLVFADVQEG GTCNASWPEP V GLWGAVFI IYTAVLGFFA PLLVICLCYL LIVVKVRAAR RQLADLEDNW ETLNDNLKVI EKADNAAQVK DALTKMRAAA LD AQKGGSG GRSPEMKDFR HGFDILVGQI DDALKLANEG KVKEAQAAAE QLKTTRNAYI QKYLERARST LRSERKVTRM VLV VVLVFA GCWLPFFTVN IVNLAVALPQ EPASAGLYFF VVILSYANSC ANPVLYGFLS DNFRQSFQKV LCL

UniProtKB: Somatostatin receptor type 5, Soluble cytochrome b562, Somatostatin receptor type 5

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Macromolecule #2: 1-[2-[[3,5-diethoxy-4-(4-fluorophenyl)phenyl]methyl]-5-oxa-2,6-di...

MacromoleculeName: 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
type: ligand / ID: 2 / Number of copies: 2 / Formula: A1EVP
Molecular weightTheoretical: 511.585 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration13.1 mg/mL
BufferpH: 7.4
GridModel: Quantifoil / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK II
Details13.1 mg/ml of the protein in a liquid buffer

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Number grids imaged: 1 / Number real images: 4619 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2700519
CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.2) / Type: NONE
Startup modelType of model: OTHER / Details: AlphaFold3-predicted model
Final reconstructionNumber classes used: 1 / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.2) / Number images used: 128653
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
Final 3D classificationNumber classes: 4 / Software - Name: cryoSPARC (ver. 4.6.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model / Details: AlphaFold3 predicted
RefinementProtocol: RIGID BODY FIT
Output model

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

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