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- PDB-7sii: Human STING bound to both cGAMP and 1-[(2-chloro-6-fluorophenyl)m... -

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Entry
Database: PDB / ID: 7sii
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)
ComponentsStimulator of interferon genes protein
KeywordsIMMUNE SYSTEM / Sting / agonist / activate conformation / oligomer
Function / homology
Function and homology information


STING complex / STAT6-mediated induction of chemokines / protein localization to endoplasmic reticulum / serine/threonine protein kinase complex / proton channel activity / 2',3'-cyclic GMP-AMP binding / STING mediated induction of host immune responses / cyclic-di-GMP binding / IRF3-mediated induction of type I IFN / positive regulation of type I interferon-mediated signaling pathway ...STING complex / STAT6-mediated induction of chemokines / protein localization to endoplasmic reticulum / serine/threonine protein kinase complex / proton channel activity / 2',3'-cyclic GMP-AMP binding / STING mediated induction of host immune responses / cyclic-di-GMP binding / 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 / autophagosome membrane / antiviral innate immune response / positive regulation of macroautophagy / cellular response to organic cyclic compound / autophagosome assembly / 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 / activation of innate immune response / Regulation of innate immune responses to cytosolic DNA / positive regulation of interferon-beta production / endoplasmic reticulum-Golgi intermediate compartment membrane / 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 / 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 / Transmembrane protein 173
Similarity search - Domain/homology
cGAMP / Chem-9IM / Stimulator of interferon genes protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.45 Å
AuthorsLu, D. / Shang, G. / Jie, L. / Lu, Y. / Bai, X.C. / Zhang, X.
Funding support United States, 6items
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 2, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 20, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 4, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jun 5, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Assembly

Deposited unit
A: Stimulator of interferon genes protein
B: Stimulator of interferon genes protein
C: Stimulator of interferon genes protein
D: Stimulator of interferon genes protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,5448
Polymers158,2144
Non-polymers2,3314
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "C"
d_1ens_2chain "B"
d_2ens_2chain "D"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1HISGLNA1 - 324
d_21ens_1HISGLNC1 - 324
d_11ens_2HISGLNB1 - 319
d_21ens_2HISGLND1 - 319

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(-0.999994280544, -0.00338196651623, 3.43724873942E-5), (0.00338195373416, -0.999994214433, -0.000365362217384), (3.56079313153E-5, -0.000365243881549, 0.999999932664)90.8380585127, 97.0882139491, 0.00696075152278
2given(-0.999999989389, -8.86665462678E-5, 0.000115589820669), (8.86648821889E-5, -0.999999995966, -1.44014589397E-5), (0.00011559109713, -1.4391210029E-5, 0.999999993216)90.7150777214, 97.1995748205, -0.00389253940705

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Components

#1: Protein
Stimulator of interferon genes protein / hSTING / Endoplasmic reticulum interferon stimulator / ERIS / Mediator of IRF3 activation / hMITA / ...hSTING / Endoplasmic reticulum interferon stimulator / ERIS / Mediator of IRF3 activation / hMITA / Transmembrane protein 173


Mass: 39553.398 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STING1, ERIS, MITA, TMEM173 / Production host: Homo sapiens (human) / References: UniProt: Q86WV6
#2: Chemical 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


Mass: 490.877 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H19ClF4N2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-1SY / cGAMP / 2',3' cGAMP / c-GMP-AMP / c[G(2',5')pA(3',5')p]


Mass: 674.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H24N10O13P2
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human STING / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: NITROGEN

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
EM softwareName: RELION / Version: 3.1 / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 231556 / Algorithm: FOURIER SPACE / Num. of class averages: 4 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 69.82 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00310546
ELECTRON MICROSCOPYf_angle_d0.469214350
ELECTRON MICROSCOPYf_chiral_restr0.03281594
ELECTRON MICROSCOPYf_plane_restr0.00321814
ELECTRON MICROSCOPYf_dihedral_angle_d12.43343846
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AELECTRON MICROSCOPYNCS constraints0.000708420047006
ens_2d_2BELECTRON MICROSCOPYNCS constraints0.000701662464985

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