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- EMDB-46700: STING oligomer bound to cGAMP, C53 and PI(3,5)P2 -

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Basic information

Entry
Database: EMDB / ID: EMD-46700
TitleSTING oligomer bound to cGAMP, C53 and PI(3,5)P2
Map data
Sample
  • Complex: STING bound to its ligand cGAMP, an engineered activator C53 and PI(3,5)P2
    • Protein or peptide: Stimulator of interferon genes protein
  • Ligand: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl di[(9Z)-octadec-9-enoate]
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: cGAMP
  • 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
KeywordsSTING / oligomer / PI(3 / 5)P2 / SIGNALING PROTEIN / SIGNALING PROTEIN-ACTIVATOR complex
Function / homology
Function and homology information


STAT6-mediated induction of chemokines / protein localization to endoplasmic reticulum / 2',3'-cyclic GMP-AMP binding / cyclic-di-GMP binding / STING mediated induction of host immune responses / positive regulation of type I interferon-mediated signaling pathway / IRF3-mediated induction of type I IFN / proton channel activity / reticulophagy / pattern recognition receptor signaling pathway ...STAT6-mediated induction of chemokines / protein localization to endoplasmic reticulum / 2',3'-cyclic GMP-AMP binding / cyclic-di-GMP binding / STING mediated induction of host immune responses / positive regulation of type I interferon-mediated signaling pathway / IRF3-mediated induction of type I IFN / proton channel activity / reticulophagy / pattern recognition receptor signaling pathway / Dengue virus activates/modulates innate and adaptive immune responses / cGAS/STING signaling pathway / cellular response to exogenous dsRNA / cytoplasmic pattern recognition receptor signaling pathway / protein complex oligomerization / positive regulation of macroautophagy / autophagosome membrane / autophagosome assembly / positive regulation of defense response to virus by host / positive regulation of type I interferon production / endoplasmic reticulum-Golgi intermediate compartment membrane / activation of innate immune response / signaling adaptor activity / positive regulation of interferon-beta production / autophagosome / cytoplasmic vesicle membrane / secretory granule membrane / Regulation of innate immune responses to cytosolic DNA / antiviral innate immune response / protein serine/threonine kinase binding / SARS-CoV-1 activates/modulates innate immune responses / peroxisome / defense response to virus / RNA polymerase II-specific DNA-binding transcription factor binding / mitochondrial outer membrane / transcription coactivator activity / endosome / Golgi membrane / innate immune response / ubiquitin protein ligase binding / Neutrophil degranulation / protein kinase binding / endoplasmic reticulum membrane / perinuclear region of cytoplasm / SARS-CoV-2 activates/modulates innate and adaptive immune responses / positive regulation of transcription by RNA polymerase II / protein homodimerization activity / identical protein binding / plasma membrane / cytosol
Similarity search - Function
: / STING transmembrane domain / : / : / 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: 2.9 Å
AuthorsLi J / Zhang X / Bai X
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA273595 United States
Welch FoundationI-1702 United States
Welch FoundationI-1944 United States
CitationJournal: Nature / Year: 2026
Title: Regulation of STING activation by phosphoinositide and cholesterol.
Authors: Jie Li / Jay Xiaojun Tan / Zhijian J Chen / Xuewu Zhang / Xiao-Chen Bai /
Abstract: Stimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA-sensing innate immune pathway. STING is activated by cyclic GMP-AMP (cGAMP) produced by the DNA sensor cGAMP ...Stimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA-sensing innate immune pathway. STING is activated by cyclic GMP-AMP (cGAMP) produced by the DNA sensor cGAMP synthase (cGAS). cGAMP-induced high-order oligomerization and translocation of STING from the endoplasmic reticulum to the Golgi and post-Golgi vesicles are critical for STING activation. Other studies have shown that phosphatidylinositol phosphates (PtdInsPs) and cholesterol also have important roles in STING activation, but the underlying mechanisms remain unclear. Here we demonstrate that cGAMP-induced high-order oligomerization of STING is enhanced strongly by phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P and PtdIns(4,5)P, and by PtdIns4P to a lesser extent. Our cryo-electron microscopy structures reveal that PtdInsPs together with cholesterol bind at the interface between STING dimers, directly promoting the high-order oligomerization. The structures also provide an explanation for the preference of the STING oligomer to different PtdInsPs. Mutational and biochemical analyses confirm the binding modes of PtdInsPs and cholesterol and their roles in STING activation. Our findings shed light on the regulatory mechanisms of STING mediated by specific lipids, which may underlie the role of intracellular trafficking in dictating STING signalling.
History
DepositionAug 22, 2024-
Header (metadata) releaseDec 17, 2025-
Map releaseDec 17, 2025-
UpdateApr 22, 2026-
Current statusApr 22, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46700.png

Downloads & links

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Map

FileDownload / File: emd_46700.map.gz / Format: CCP4 / Size: 115.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 312 pix.
= 257.899 Å		0.83 Å/pix.
x 312 pix.
= 257.899 Å		0.83 Å/pix.
x 312 pix.
= 257.899 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8266 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.0138814775 - 0.0377643
Average (Standard dev.)0.0001645961 (±0.0011629097)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions312312312
Spacing312312312
CellA=B=C: 257.8992 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_46700_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_46700_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : STING bound to its ligand cGAMP, an engineered activator C53 and ...

EntireName: STING bound to its ligand cGAMP, an engineered activator C53 and PI(3,5)P2
Components
  • Complex: STING bound to its ligand cGAMP, an engineered activator C53 and PI(3,5)P2
    • Protein or peptide: Stimulator of interferon genes protein
  • Ligand: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl di[(9Z)-octadec-9-enoate]
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: cGAMP
  • 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: STING bound to its ligand cGAMP, an engineered activator C53 and ...

SupramoleculeName: STING bound to its ligand cGAMP, an engineered activator C53 and PI(3,5)P2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 39.553398 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 TGDRAGIKDR VY SNSIYEL LENGQRAGTC VLEYATPLQT LFAMSQYSQA GFSREDRLEQ AKLFCRTLED ILADAPESQN NCRLIAYQEP ADD SSFSLS QEVLRHLRQE EKEEVTVGTS SGLEVLFQ

UniProtKB: Stimulator of interferon genes protein

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Macromolecule #2: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bi...

MacromoleculeName: (2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl di[(9Z)-octadec-9-enoate]
type: ligand / ID: 2 / Number of copies: 2 / Formula: A1BBH
Molecular weightTheoretical: 1.023066 KDa

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #4: cGAMP

MacromoleculeName: cGAMP / type: ligand / ID: 4 / Number of copies: 2 / Formula: 1SY
Molecular weightTheoretical: 674.411 Da
Chemical component information

ChemComp-1SY:
cGAMP

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Macromolecule #5: 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: 5 / 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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

29282

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 219323
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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