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- EMDB-29281: Cryo-EM structure of STING oligomer bound to cGAMP and NVS-STG2 -

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Basic information

Entry
Database: EMDB / ID: EMD-29281
TitleCryo-EM structure of STING oligomer bound to cGAMP and NVS-STG2
Map dataMap of STING tetramer bound to cGAMP and NVS-STG2
Sample
  • Complex: STING tetramer
    • Protein or peptide: Stimulator of interferon genes protein
  • Ligand: cGAMP
  • Ligand: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid
KeywordsSTING / innate immunity / molecular glue / 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: 4.0 Å
AuthorsLi J / Canham SM / Zhang X / Bai X / Feng Y
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM130289 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM143158 United States
Robert A. Welch FoundationI-1702 United States
Robert A. Welch FoundationI-1944 United States
CitationJournal: Nat Chem Biol / Year: 2024
Title: Activation of human STING by a molecular glue-like compound.
Authors: Jie Li / Stephen M Canham / Hua Wu / Martin Henault / Lihao Chen / Guoxun Liu / Yu Chen / Gary Yu / Howard R Miller / Viktor Hornak / Scott M Brittain / Gregory A Michaud / Antonin Tutter / ...Authors: Jie Li / Stephen M Canham / Hua Wu / Martin Henault / Lihao Chen / Guoxun Liu / Yu Chen / Gary Yu / Howard R Miller / Viktor Hornak / Scott M Brittain / Gregory A Michaud / Antonin Tutter / Wendy Broom / Mary Ellen Digan / Sarah M McWhirter / Kelsey E Sivick / Helen T Pham / Christine H Chen / George S Tria / Jeffery M McKenna / Markus Schirle / Xiaohong Mao / Thomas B Nicholson / Yuan Wang / Jeremy L Jenkins / Rishi K Jain / John A Tallarico / Sejal J Patel / Lianxing Zheng / Nathan T Ross / Charles Y Cho / Xuewu Zhang / Xiao-Chen Bai / Yan Feng /
Abstract: Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its ...Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.
History
DepositionDec 21, 2022-
Header (metadata) releaseNov 1, 2023-
Map releaseNov 1, 2023-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29281.png

Downloads & links

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Map

FileDownload / File: emd_29281.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap of STING tetramer bound to cGAMP and NVS-STG2
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 160 pix.
= 172.8 Å		1.08 Å/pix.
x 160 pix.
= 172.8 Å		1.08 Å/pix.
x 160 pix.
= 172.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.018094148 - 0.03851666
Average (Standard dev.)0.0005096205 (±0.0019860493)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 172.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map 1

Fileemd_29281_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_29281_half_map_2.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : STING tetramer

EntireName: STING tetramer
Components
  • Complex: STING tetramer
    • Protein or peptide: Stimulator of interferon genes protein
  • Ligand: cGAMP
  • Ligand: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid

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Supramolecule #1: STING tetramer

SupramoleculeName: STING tetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: STING tetramer, which can further assemblies into larger oligomers, induced by cGAMP and NVS-STG2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 300 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: 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: cGAMP

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

ChemComp-1SY:
cGAMP

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Macromolecule #3: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}a...

MacromoleculeName: 4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid
type: ligand / ID: 3 / Number of copies: 2 / Formula: Y6H
Molecular weightTheoretical: 427.533 Da
Chemical component information

ChemComp-Y6H:
4-({[4-(2-tert-butyl-5,5-dimethyl-1,3-dioxan-2-yl)phenyl]methyl}amino)-3-methoxybenzoic acid

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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: 7.5
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 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: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

25142

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 117249
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-8flk:
Cryo-EM structure of STING oligomer bound to cGAMP and NVS-STG2

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