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- EMDB-25142: Human STING bound to both cGAMP and 1-[(2-chloro-6-fluorophenyl)m... -

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Basic information

Entry
Database: EMDB / ID: EMD-25142
TitleHuman STING bound to both cGAMP and 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide (Compound 53)
Map data
Sample
  • Complex: human STING
    • Protein or peptide: Stimulator of interferon genes protein
  • 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
  • Ligand: cGAMPCyclic guanosine monophosphate–adenosine monophosphate
KeywordsSting / agonist / activate conformation / oligomer / IMMUNE SYSTEM
Function / homology
Function and homology information


STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / 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 ...STING complex / STAT6-mediated induction of chemokines / serine/threonine protein kinase complex / 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 / cellular response to exogenous dsRNA / cytoplasmic pattern recognition receptor signaling pathway / autophagosome membrane / antiviral innate immune response / positive regulation of macroautophagy / autophagosome assembly / cellular response to organic cyclic compound / autophagosome / positive regulation of type I interferon production / cellular response to interferon-beta / signaling adaptor activity / positive regulation of defense response to virus by host / Regulation of innate immune responses to cytosolic DNA / endoplasmic reticulum-Golgi intermediate compartment membrane / activation of innate immune response / positive regulation of interferon-beta production / secretory granule membrane / cytoplasmic vesicle membrane / positive regulation of DNA-binding transcription factor activity / peroxisome / SARS-CoV-1 activates/modulates innate immune responses / positive regulation of protein binding / protein complex oligomerization / regulation of inflammatory response / defense response to virus / mitochondrial outer membrane / RNA polymerase II-specific DNA-binding transcription factor binding / 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 / Transmembrane protein 173
Similarity search - Domain/homology
Stimulator of interferon genes protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.45 Å
AuthorsLu D / Shang G
Funding support United States, 6 items
OrganizationGrant numberCountry
Robert A. Welch FoundationI-1702 United States
Robert A. Welch FoundationI-1944 United States
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
Cancer Prevention and Research Institute of Texas (CPRIT)RP160082 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP170644 United States
CitationJournal: Nature / Year: 2022
Title: Activation of STING by targeting a pocket in the transmembrane domain.
Authors: Defen Lu / Guijun Shang / Jie Li / Yong Lu / Xiao-Chen Bai / Xuewu Zhang /
Abstract: Stimulator of interferon genes (STING) is an adaptor protein in innate immunity against DNA viruses or bacteria. STING-mediated immunity could be exploited in the development of vaccines or cancer ...Stimulator of interferon genes (STING) is an adaptor protein in innate immunity against DNA viruses or bacteria. STING-mediated immunity could be exploited in the development of vaccines or cancer immunotherapies. STING is a transmembrane dimeric protein that is located in the endoplasmic reticulum or in the Golgi apparatus. STING is activated by the binding of its cytoplasmic ligand-binding domain to cyclic dinucleotides that are produced by the DNA sensor cyclic GMP-AMP (cGAMP) synthase or by invading bacteria. Cyclic dinucleotides induce a conformational change in the STING ligand-binding domain, which leads to a high-order oligomerization of STING that is essential for triggering the downstream signalling pathways. However, the cGAMP-induced STING oligomers tend to dissociate in solution and have not been resolved to high resolution, which limits our understanding of the activation mechanism. Here we show that a small-molecule agonist, compound 53 (C53), promotes the oligomerization and activation of human STING through a mechanism orthogonal to that of cGAMP. We determined a cryo-electron microscopy structure of STING bound to both C53 and cGAMP, revealing a stable oligomer that is formed by side-by-side packing and has a curled overall shape. Notably, C53 binds to a cryptic pocket in the STING transmembrane domain, between the two subunits of the STING dimer. This binding triggers outward shifts of transmembrane helices in the dimer, and induces inter-dimer interactions between these helices to mediate the formation of the high-order oligomer. Our functional analyses show that cGAMP and C53 together induce stronger activation of STING than either ligand alone.
History
DepositionOct 14, 2021-
Header (metadata) releaseFeb 2, 2022-
Map releaseFeb 2, 2022-
UpdateJun 5, 2024-
Current statusJun 5, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with fitted model
  • Atomic models: PDB-7sii
  • Surface level: 0.018
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-7sii
  • Surface level: 0.018
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_25142.png

Downloads & links

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Map

FileDownload / File: emd_25142.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.018 / Movie #1: 0.018
Minimum - Maximum-0.071872756 - 0.12827747
Average (Standard dev.)0.0000930668 (±0.006411415)
SymmetrySpace group: 1
Details

EMDB XML:

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

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z160160160
origin x/y/z0.0000.0000.000
length x/y/z172.800172.800172.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS160160160
D min/max/mean-0.0720.1280.000

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Supplemental data

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Sample components

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Entire : human STING

EntireName: human STING
Components
  • Complex: human STING
    • Protein or peptide: Stimulator of interferon genes protein
  • 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
  • Ligand: cGAMPCyclic guanosine monophosphate–adenosine monophosphate

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Supramolecule #1: human STING

SupramoleculeName: human STING / 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: 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: 2 / 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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Macromolecule #3: cGAMP

MacromoleculeName: cGAMP / type: ligand / ID: 3 / Number of copies: 2 / Formula: 1SY
Molecular weightTheoretical: 674.411 Da
Chemical component information

ChemComp-1SY:
cGAMP / Cyclic guanosine monophosphate–adenosine monophosphate

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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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionNumber classes used: 4 / Applied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 231556
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-7sii:
Human STING bound to both cGAMP and 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide (Compound 53)

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