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- PDB-7mhc: Structure of human STING in complex with MK-1454 -

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Basic information

Entry
Database: PDB / ID: 7mhc
TitleStructure of human STING in complex with MK-1454
ComponentsStimulator of interferon genes protein
KeywordsIMMUNE SYSTEM / STING / RECEPTOR / LIGAND COMPLEX / AGONIST / CLOSED CONFORMATION
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-ZEV / Stimulator of interferon genes protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.32 Å
AuthorsLesburg, C.A.
CitationJournal: Nature / Year: 2022
Title: A kinase-cGAS cascade to synthesize a therapeutic STING activator.
Authors: McIntosh, J.A. / Liu, Z. / Andresen, B.M. / Marzijarani, N.S. / Moore, J.C. / Marshall, N.M. / Borra-Garske, M. / Obligacion, J.V. / Fier, P.S. / Peng, F. / Forstater, J.H. / Winston, M.S. / ...Authors: McIntosh, J.A. / Liu, Z. / Andresen, B.M. / Marzijarani, N.S. / Moore, J.C. / Marshall, N.M. / Borra-Garske, M. / Obligacion, J.V. / Fier, P.S. / Peng, F. / Forstater, J.H. / Winston, M.S. / An, C. / Chang, W. / Lim, J. / Huffman, M.A. / Miller, S.P. / Tsay, F.R. / Altman, M.D. / Lesburg, C.A. / Steinhuebel, D. / Trotter, B.W. / Cumming, J.N. / Northrup, A. / Bu, X. / Mann, B.F. / Biba, M. / Hiraga, K. / Murphy, G.S. / Kolev, J.N. / Makarewicz, A. / Pan, W. / Farasat, I. / Bade, R.S. / Stone, K. / Duan, D. / Alvizo, O. / Adpressa, D. / Guetschow, E. / Hoyt, E. / Regalado, E.L. / Castro, S. / Rivera, N. / Smith, J.P. / Wang, F. / Crespo, A. / Verma, D. / Axnanda, S. / Dance, Z.E.X. / Devine, P.N. / Tschaen, D. / Canada, K.A. / Bulger, P.G. / Sherry, B.D. / Truppo, M.D. / Ruck, R.T. / Campeau, L.C. / Bennett, D.J. / Humphrey, G.R. / Campos, K.R. / Maddess, M.L.
History
DepositionApr 15, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2642
Polymers21,5551
Non-polymers7091
Water50428
1
A: Stimulator of interferon genes protein
hetero molecules

A: Stimulator of interferon genes protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5274
Polymers43,1102
Non-polymers1,4172
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_654-x+1,y,-z-11
Buried area4270 Å2
ΔGint-21 kcal/mol
Surface area16270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.120, 72.740, 36.370
Angle α, β, γ (deg.)90.000, 100.970, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-517-

HOH

21A-528-

HOH

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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: 21555.191 Da / Num. of mol.: 1 / Mutation: G230A, H232R, R293Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STING1, ERIS, MITA, TMEM173 / Production host: Escherichia coli (E. coli) / References: UniProt: Q86WV6
#2: Chemical ChemComp-ZEV / (2R,5R,7R,8S,10R,12aR,14R,15S,15aR,16R)-7-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-14-(6-amino-9H-purin-9-yl)-15,16-difluoro-2,10-bis(sulfanyl)octahydro-2H,10H,12H-5,8-methano-2lambda~5~,10lambda~5~-furo[3,2-l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecine-2,10-dione


Mass: 708.509 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C20H20F2N10O9P2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 2.65 Å3/Da / Density % sol: 53.66 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1 M TRIS; 0.2 M NaCl; 28.0 w/v PEG 6K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 23, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.32→35.7 Å / Num. obs: 9280 / % possible obs: 94.5 % / Redundancy: 3.3 % / Biso Wilson estimate: 62.71 Å2 / CC1/2: 0.999 / Rpim(I) all: 0.028 / Rrim(I) all: 0.052 / Net I/σ(I): 13.4
Reflection shellResolution: 2.321→2.329 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 2.1 / Num. measured all: 4931 / Num. unique obs: 1422 / CC1/2: 0.894 / Rpim(I) all: 0.309 / Rrim(I) all: 0.586 / Net I/σ(I) obs: 1.9 / % possible all: 98

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
Aimless0.5.21data scaling
PDB_EXTRACT3.27data extraction
BUSTERphasing
XDSdata processing
XDSdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4ksy

4ksy


Resolution: 2.32→35.7 Å / Cor.coef. Fo:Fc: 0.9439 / Cor.coef. Fo:Fc free: 0.9261 / SU R Cruickshank DPI: 0.315 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.298 / SU Rfree Blow DPI: 0.208 / SU Rfree Cruickshank DPI: 0.214
RfactorNum. reflection% reflectionSelection details
Rfree0.2243 488 5.26 %RANDOM
Rwork0.1919 ---
obs0.1935 9279 94.37 %-
Displacement parametersBiso max: 185.78 Å2 / Biso mean: 72.53 Å2 / Biso min: 36.33 Å2
Baniso -1Baniso -2Baniso -3
1-4.4208 Å20 Å2-15.1166 Å2
2---4.5729 Å20 Å2
3---0.1521 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.32→35.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1445 0 65 28 1538
Biso mean--45.29 64.02 -
Num. residues----179
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d545SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes45HARMONIC2
X-RAY DIFFRACTIONt_gen_planes250HARMONIC5
X-RAY DIFFRACTIONt_it1543HARMONIC20
X-RAY DIFFRACTIONt_chiral_improper_torsion194SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1631SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1543HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2123HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion2.96
X-RAY DIFFRACTIONt_other_torsion19.02
LS refinement shellResolution: 2.32→2.59 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.3075 143 5.18 %
Rwork0.2121 2619 -
all0.2166 2762 -
obs--99.03 %
Refinement TLS params.Method: refined / Origin x: 34.986 Å / Origin y: 6.078 Å / Origin z: -19.4144 Å
111213212223313233
T-0.0764 Å20.0161 Å20.0552 Å2--0.0127 Å2-0.0135 Å2---0.099 Å2
L1.3306 °2-0.6178 °2-0.2363 °2-1.9913 °2-0.031 °2--1.7955 °2
S-0.0244 Å °0.0835 Å °0.0537 Å °-0.0056 Å °0.0185 Å °0.1434 Å °-0.0295 Å °-0.2921 Å °0.0058 Å °
Refinement TLS groupSelection details: { A|* }

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