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- PDB-8p01: Crystal structure of human STING ectodomain in complex with BI 74... -

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Basic information

Entry
Database: PDB / ID: 8p01
TitleCrystal structure of human STING ectodomain in complex with BI 7446, a potent cyclic dinucleotide STING agonist with broad-spectrum variant activity for the treatment of cancer
ComponentsStimulator of interferon genes protein
KeywordsIMMUNE SYSTEM / agonist / complex / innate immune response
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
Chem-W78 / Stimulator of interferon genes protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.094 Å
AuthorsNar, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of BI 7446: A Potent Cyclic Dinucleotide STING Agonist with Broad-Spectrum Variant Activity for the Treatment of Cancer.
Authors: Kuttruff, C.A. / Fleck, M. / Carotta, S. / Arnhof, H. / Bretschneider, T. / Dahmann, G. / Gremel, G. / Grube, A. / Handschuh, S. / Heimann, A. / Hofmann, M.H. / Impagnatiello, M.A. / Nar, H. ...Authors: Kuttruff, C.A. / Fleck, M. / Carotta, S. / Arnhof, H. / Bretschneider, T. / Dahmann, G. / Gremel, G. / Grube, A. / Handschuh, S. / Heimann, A. / Hofmann, M.H. / Impagnatiello, M.A. / Nar, H. / Rast, G. / Schaaf, O. / Schmidt, E. / Oost, T.
History
DepositionMay 9, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 26, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: 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 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Stimulator of interferon genes protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,0372
Polymers28,3441
Non-polymers6941
Water54030
1
A: Stimulator of interferon genes protein
hetero molecules

A: Stimulator of interferon genes protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,0754
Polymers56,6882
Non-polymers1,3872
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_654-x+1,y,-z-11
Buried area4340 Å2
ΔGint-18 kcal/mol
Surface area16050 Å2
Unit cell
Length a, b, c (Å)89.698, 77.593, 35.975
Angle α, β, γ (deg.)90, 98.08, 90
Int Tables number5
Space group name H-MC121

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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: 28343.816 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STING1, ERIS, MITA, STING, TMEM173 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q86WV6
#2: Chemical ChemComp-W78 / 3-[(1~{R},3~{R},6~{R},8~{R},9~{R},10~{R},12~{R},15~{R},17~{R},18~{R})-8-(6-aminopurin-9-yl)-9-fluoranyl-18-oxidanyl-3,12-bis(oxidanylidene)-3,12-bis(sulfanyl)-2,4,7,11,13,16-hexaoxa-3$l^{5},12$l^{5}-diphosphatricyclo[13.2.1.0^{6,10}]octadecan-17-yl]-6~{H}-imidazo[4,5-d]pyridazin-7-one


Mass: 693.519 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22FN9O10P2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 30 / 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

CrystalDensity Matthews: 2.19 Å3/Da / Density % sol: 43.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 20% polyethelene glycol 3350, 200mM tri-sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Aug 30, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.094→58.43 Å / Num. obs: 9077 / % possible obs: 62.8 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.051 / Rsym value: 0.051 / Net I/σ(I): 17.2
Reflection shellResolution: 2.094→2.332 Å / Redundancy: 6.4 % / Rmerge(I) obs: 1.288 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 452 / Rsym value: 1.288 / % possible all: 11.4

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata reduction
XDSMay 1, 2016data reduction
autoPROC1.1.7data scaling
Aimlessdata scaling
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.094→58.43 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.923 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.405 / SU Rfree Blow DPI: 0.256
RfactorNum. reflection% reflectionSelection details
Rfree0.2623 422 -RANDOM
Rwork0.2401 ---
obs0.2411 9077 62.8 %-
Displacement parametersBiso mean: 76.29 Å2
Baniso -1Baniso -2Baniso -3
1--5.0753 Å20 Å23.591 Å2
2--4.2326 Å20 Å2
3---0.8427 Å2
Refine analyzeLuzzati coordinate error obs: 0.4 Å
Refinement stepCycle: LAST / Resolution: 2.094→58.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1465 0 44 30 1539
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0073002HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.895395HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d918SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes484HARMONIC5
X-RAY DIFFRACTIONt_it1543HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion197SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2380SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.57
X-RAY DIFFRACTIONt_other_torsion16.18
LS refinement shellResolution: 2.094→2.33 Å
RfactorNum. reflection% reflection
Rfree0.3106 18 -
Rwork0.323 --
obs--11.05 %
Refinement TLS params.Origin x: 34.3792 Å / Origin y: 4.4731 Å / Origin z: -18.5045 Å
111213212223313233
T-0.1578 Å2-0.0425 Å20.0523 Å2-0.0534 Å2-0.0892 Å2--0.0591 Å2
L4.5359 °2-0.9567 °20.0378 °2-5.9104 °20.5755 °2--3.0415 °2
S0.098 Å °-0.2392 Å °0.2367 Å °-0.2392 Å °-0.1168 Å °-0.5097 Å °0.2367 Å °-0.5097 Å °0.0188 Å °
Refinement TLS groupSelection details: { A|* }

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