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- EMDB-45897: HsSTING with SR-717 and C53 -

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Basic information

Entry
Database: EMDB / ID: EMD-45897
TitleHsSTING with SR-717 and C53
Map data
Sample
  • Complex: Stimulator of interferon genes
    • Protein or peptide: Stimulator of interferon genes protein
  • Ligand: 4,5-difluoro-2-{[6-(1H-imidazol-1-yl)pyridazine-3-carbonyl]amino}benzoic acid
  • Ligand: 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide
KeywordsInnate immunity / membrane protein / IMMUNE SYSTEM
Function / homology
Function and homology information


STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / protein localization to endoplasmic reticulum / 2',3'-cyclic GMP-AMP binding / proton channel activity / cyclic-di-GMP binding / STING mediated induction of host immune responses / IRF3-mediated induction of type I IFN / positive regulation of type I interferon-mediated signaling pathway ...STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / protein localization to endoplasmic reticulum / 2',3'-cyclic GMP-AMP binding / proton channel activity / cyclic-di-GMP binding / STING mediated induction of host immune responses / IRF3-mediated induction of type I IFN / positive regulation of type I interferon-mediated signaling pathway / cGAS/STING signaling pathway / reticulophagy / pattern recognition receptor signaling pathway / cytoplasmic pattern recognition receptor signaling pathway / cellular response to exogenous dsRNA / protein complex oligomerization / positive regulation of macroautophagy / autophagosome membrane / : / autophagosome assembly / positive regulation of type I interferon production / cellular response to interferon-beta / signaling adaptor activity / positive regulation of defense response to virus by host / antiviral innate immune response / cytoplasmic vesicle membrane / endoplasmic reticulum-Golgi intermediate compartment membrane / Regulation of innate immune responses to cytosolic DNA / activation of innate immune response / autophagosome / positive regulation of interferon-beta production / secretory granule membrane / positive regulation of DNA-binding transcription factor activity / SARS-CoV-1 activates/modulates innate immune responses / peroxisome / positive regulation of protein binding / regulation of inflammatory response / defense response to virus / RNA polymerase II-specific DNA-binding transcription factor binding / mitochondrial outer membrane / endosome / Golgi membrane / innate immune response / ubiquitin protein ligase binding / Neutrophil degranulation / endoplasmic reticulum membrane / protein kinase binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / perinuclear region of cytoplasm / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / plasma membrane / cytosol
Similarity search - Function
: / Stimulator of interferon genes protein / Stimulator of interferon genes protein, C-terminal domain superfamily / STING ligand-binding domain
Similarity search - Domain/homology
Stimulator of interferon genes protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsGharpure A / Sulpizio A / Lairson LL / Ward AB
Funding support1 items
OrganizationGrant numberCountry
Other government
CitationJournal: Nat Commun / Year: 2025
Title: Distinct oligomeric assemblies of STING induced by non-nucleotide agonists.
Authors: Anant Gharpure / Ariana Sulpizio / Johannes R Loeffler / Monica L Fernández-Quintero / Andy S Tran / Luke L Lairson / Andrew B Ward /
Abstract: STING plays essential roles coordinating innate immune responses to processes that range from pathogenic infection to genomic instability. Its adaptor function is activated by cyclic dinucleotide ...STING plays essential roles coordinating innate immune responses to processes that range from pathogenic infection to genomic instability. Its adaptor function is activated by cyclic dinucleotide (CDN) secondary messengers originating from self (2'3'-cGAMP) or bacterial sources (3'3'-CDNs). Different classes of CDNs possess distinct binding modes, stabilizing STING's ligand-binding domain (LBD) in either a closed or open conformation. The closed conformation, induced by the endogenous ligand 2'3'-cGAMP, has been extensively studied using cryo-EM. However, significant questions remain regarding the structural basis of STING activation by open conformation-inducing ligands. Using cryo-EM, we investigate potential differences in conformational changes and oligomeric assemblies of STING for closed and open conformation-inducing synthetic agonists. While we observe a characteristic 180° rotation for both classes, the open-LBD inducing agonist diABZI-3 uniquely induces a quaternary structure reminiscent but distinct from the reported autoinhibited state of apo-STING. Additionally, we observe slower rates of activation for this ligand class in functional assays, which collectively suggests the existence of a potential additional regulatory mechanism for open conformation-inducing ligands that involves head-to-head interactions and restriction of curved oligomer formation. These observations have potential implications in the selection of an optimal class of STING agonist in the context of a defined therapeutic application.
History
DepositionJul 24, 2024-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateApr 23, 2025-
Current statusApr 23, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45897.png

Downloads & links

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Map

FileDownload / File: emd_45897.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.72 Å/pix.
x 320 pix.
= 229.76 Å		0.72 Å/pix.
x 320 pix.
= 229.76 Å		0.72 Å/pix.
x 320 pix.
= 229.76 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.718 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.5870964 - 0.86589426
Average (Standard dev.)0.0006485423 (±0.02397568)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 229.76 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_45897_half_map_1.map
Projections & Slices
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Histogram

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Half map: #1

Fileemd_45897_half_map_2.map
Projections & Slices
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Sample components

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Entire : Stimulator of interferon genes

EntireName: Stimulator of interferon genes
Components
  • Complex: Stimulator of interferon genes
    • Protein or peptide: Stimulator of interferon genes protein
  • Ligand: 4,5-difluoro-2-{[6-(1H-imidazol-1-yl)pyridazine-3-carbonyl]amino}benzoic acid
  • Ligand: 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide

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Supramolecule #1: Stimulator of interferon genes

SupramoleculeName: Stimulator of interferon genes / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 400 KDa

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Macromolecule #1: Stimulator of interferon genes protein

MacromoleculeName: Stimulator of interferon genes protein / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.246 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPHSSLHPSI PCPRGHGAQK AALVLLSACL VTLWGLGEPP EHTLRYLVLH LASLQLGLLL NGVCSLAEEL RHIHSRYRGS YWRTVRACL GCPLRRGALL LLSIYFYYSL PNAVGPPFTW MLALLGLSQA LNILLGLKGL APAEISAVCE KGNFNVAHGL A WSYYIGYL ...String:
MPHSSLHPSI PCPRGHGAQK AALVLLSACL VTLWGLGEPP EHTLRYLVLH LASLQLGLLL NGVCSLAEEL RHIHSRYRGS YWRTVRACL GCPLRRGALL LLSIYFYYSL PNAVGPPFTW MLALLGLSQA LNILLGLKGL APAEISAVCE KGNFNVAHGL A WSYYIGYL RLILPELQAR IRTYNQHYNN LLRGAVSQRL YILLPLDCGV PDNLSMADPN IRFLDKLPQQ TGDHAGIKDR VY SNSIYEL LENGQRAGTC VLEYATPLQT LFAMSQYSQA GFSREDRLEQ AKLFCRTLED ILADAPESQN NCRLIAYQEP ADD SSFSLS QEVLRHLRQE EKEEVTVGGG SGGGSGGSAW SHPQFEK

UniProtKB: Stimulator of interferon genes protein

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Macromolecule #2: 4,5-difluoro-2-{[6-(1H-imidazol-1-yl)pyridazine-3-carbonyl]amino}...

MacromoleculeName: 4,5-difluoro-2-{[6-(1H-imidazol-1-yl)pyridazine-3-carbonyl]amino}benzoic acid
type: ligand / ID: 2 / Number of copies: 4 / Formula: V67
Molecular weightTheoretical: 345.26 Da
Chemical component information

ChemComp-V67:
4,5-difluoro-2-{[6-(1H-imidazol-1-yl)pyridazine-3-carbonyl]amino}benzoic acid

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Macromolecule #3: 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-...

MacromoleculeName: 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide
type: ligand / ID: 3 / Number of copies: 2 / Formula: 9IM
Molecular weightTheoretical: 490.877 Da
Chemical component information

ChemComp-9IM:
1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide

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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

Concentration8 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMC4H11NO3Tris
150.0 mMNaClSodium Chloride
0.5 mMC9H15O6PTCEP
0.02 %C24H46O11Dodecyl maltoside
0.004 %C31H50O4Cholesteryl hemisuccinate
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number real images: 4818 / Average exposure time: 2.2 sec. / Average electron dose: 45.07 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 20.0 µm / Illumination mode: SPOT SCAN / Imaging mode: OTHER / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 190000
Sample stageCooling holder cryogen: NITROGEN

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7sii


Details: Low-pass filtered to 20 A
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 272478
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC

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Atomic model buiding 1

Initial modelPDB ID:

7sii


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9ct3:
HsSTING with SR-717 and C53

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