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- PDB-8a2k: human STING in complex with 2'-3'-cyclic-GMP-7-deaza(4-[(2-naphth... -

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Basic information

Entry
Database: PDB / ID: 8a2k
Titlehuman STING in complex with 2'-3'-cyclic-GMP-7-deaza(4-[(2-naphthyloxy)methyl]phenyl)-AMP
ComponentsStimulator of interferon genes protein
KeywordsIMMUNE SYSTEM / Complex / STING / cyclic dinucleotide
Function / homology
Function and homology information


STING complex / 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 / serine/threonine protein kinase complex / positive regulation of type I interferon-mediated signaling pathway / IRF3-mediated induction of type I IFN / cGAS/STING signaling pathway ...STING complex / 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 / serine/threonine protein kinase complex / positive regulation of type I interferon-mediated signaling pathway / IRF3-mediated induction of type I IFN / cGAS/STING signaling pathway / proton channel activity / pattern recognition receptor signaling pathway / reticulophagy / cytoplasmic pattern recognition receptor signaling pathway / cellular response to exogenous dsRNA / protein complex oligomerization / autophagosome membrane / positive regulation of macroautophagy / autophagosome assembly / positive regulation of type I interferon production / positive regulation of DNA-binding transcription factor activity / cellular response to interferon-beta / positive regulation of defense response to virus by host / signaling adaptor activity / antiviral innate immune response / endoplasmic reticulum-Golgi intermediate compartment membrane / activation of innate immune response / Regulation of innate immune responses to cytosolic DNA / protein serine/threonine kinase binding / positive regulation of interferon-beta production / autophagosome / cytoplasmic vesicle membrane / secretory granule membrane / SARS-CoV-1 activates/modulates innate immune responses / peroxisome / regulation of inflammatory response / defense response to virus / DNA-binding transcription factor binding / RNA polymerase II-specific DNA-binding transcription factor binding / mitochondrial outer membrane / endosome / cilium / ciliary basal body / Golgi membrane / innate immune response / ubiquitin protein ligase binding / Neutrophil degranulation / endoplasmic reticulum membrane / protein kinase binding / perinuclear region of cytoplasm / SARS-CoV-2 activates/modulates innate and adaptive immune responses / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / 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
Chem-KXD / Stimulator of interferon genes protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 Å
AuthorsVavrina, Z. / Brynda, J. / Rezacova, P.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Regional Development FundCZ.02.1.01/0.0/0.0/16_019/0000729European Union
CitationJournal: J.Med.Chem. / Year: 2022
Title: Design, Synthesis, and Biochemical and Biological Evaluation of Novel 7-Deazapurine Cyclic Dinucleotide Analogues as STING Receptor Agonists.
Authors: Vavrina, Z. / Perlikova, P. / Milisavljevic, N. / Chevrier, F. / Smola, M. / Smith, J. / Dejmek, M. / Havlicek, V. / Budesinsky, M. / Liboska, R. / Vanekova, L. / Brynda, J. / Boura, E. / ...Authors: Vavrina, Z. / Perlikova, P. / Milisavljevic, N. / Chevrier, F. / Smola, M. / Smith, J. / Dejmek, M. / Havlicek, V. / Budesinsky, M. / Liboska, R. / Vanekova, L. / Brynda, J. / Boura, E. / Rezacova, P. / Hocek, M. / Birkus, G.
History
DepositionJun 3, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 12, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2022Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 9, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)55,1013
Polymers54,1952
Non-polymers9061
Water2,684149
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)93.902, 117.256, 35.884
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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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: 27097.514 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STING1, ERIS, MITA, STING, TMEM173 / Production host: Escherichia coli (E. coli) / References: UniProt: Q86WV6
#2: Chemical ChemComp-KXD / 2-azanyl-9-[(1~{R},6~{R},8~{R},9~{R},10~{S},15~{R},17~{R},18~{R})-8-[4-azanyl-5-[4-(naphthalen-1-yloxymethyl)phenyl]pyrrolo[2,3-d]pyrimidin-7-yl]-3,9,12,18-tetrakis(oxidanyl)-3,12-bis(oxidanylidene)-2,4,7,11,13,16-hexaoxa-3$l^{5},12$l^{5}-diphosphatricyclo[13.2.1.0^{6,10}]octadecan-17-yl]-3~{H}-purin-6-one


Mass: 905.700 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H37N9O14P2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 149 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 100 mM PIPES [pH 7.0], 100 mM magnesium formate dihydrate, 100 mM rubidium chloride, 25% (w/v) PEG smear high, 10 mM EDTA, 100 mM tri-sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 8, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.89→49.73 Å / Num. obs: 32651 / % possible obs: 99.9 % / Redundancy: 7.921 % / Biso Wilson estimate: 31.4 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.135 / Rrim(I) all: 0.145 / Χ2: 0.805 / Net I/σ(I): 11.01 / Num. measured all: 258640
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.89-27.7391.7121.0340047518551750.4211.83699.8
2-2.148.0740.9492.0139238486348600.721.01599.9
2.14-2.318.2790.5593.5537753456145600.9060.597100
2.31-2.538.0320.3765.2233935422542250.9520.402100
2.53-2.837.9130.2398.0630220381938190.9770.256100
2.83-3.278.270.13514.528433344034380.9930.14599.9
3.27-47.4250.07225.9121496290528950.9980.07899.7
4-5.647.8470.04641.0418010229522950.9990.049100
5.64-49.736.870.03540.639508138813840.9990.03899.7

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4KSY

4ksy


Resolution: 1.89→49.73 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2599 1632 5 %
Rwork0.2154 --
obs0.2176 32622 99.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 98.02 Å2 / Biso mean: 36.4184 Å2 / Biso min: 19.56 Å2
Refinement stepCycle: final / Resolution: 1.89→49.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2740 0 63 150 2953
Biso mean--38.67 42.89 -
Num. residues----361
LS refinement shellResolution: 1.8896→1.9572 Å
RfactorNum. reflection% reflection
Rfree0.3766 159 -
Rwork0.3454 --
all-3021 -
obs--99.7 %

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