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- PDB-6xf3: Crystal structure of STING in complex with E7766 -

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Basic information

Entry
Database: PDB / ID: 6xf3
TitleCrystal structure of STING in complex with E7766
ComponentsStimulator of interferon genes protein
KeywordsIMMUNE SYSTEM / Stimulator of interferon genes (STING) / E7766 / Agonist / Macrocycle
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-V5V / Stimulator of interferon genes protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
AuthorsChen, Y. / Wang, J.Y. / Kim, D.-S.
CitationJournal: Chemmedchem / Year: 2021
Title: E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity.
Authors: Kim, D.S. / Endo, A. / Fang, F.G. / Huang, K.C. / Bao, X. / Choi, H.W. / Majumder, U. / Shen, Y.Y. / Mathieu, S. / Zhu, X. / Sanders, K. / Noland, T. / Hao, M.H. / Chen, Y. / Wang, J.Y. / ...Authors: Kim, D.S. / Endo, A. / Fang, F.G. / Huang, K.C. / Bao, X. / Choi, H.W. / Majumder, U. / Shen, Y.Y. / Mathieu, S. / Zhu, X. / Sanders, K. / Noland, T. / Hao, M.H. / Chen, Y. / Wang, J.Y. / Yasui, S. / TenDyke, K. / Wu, J. / Ingersoll, C. / Loiacono, K.A. / Hutz, J.E. / Sarwar, N.
History
DepositionJun 15, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 16, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)43,9473
Polymers43,2012
Non-polymers7471
Water2,342130
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3420 Å2
ΔGint-18 kcal/mol
Surface area16280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)33.820, 78.110, 132.212
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: GLU / End label comp-ID: GLU / Refine code: _ / Auth seq-ID: 154 - 337 / Label seq-ID: 2 - 185

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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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: 21600.256 Da / Num. of mol.: 2
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-V5V / (1R,3R,15E,28R,29R,30R,31R,34R,36R,39S,41R)-29,41-difluoro-34,39-disulfanyl-2,33,35,38,40,42-hexaoxa-4,6,9,11,13,18,20,22,25,27-decaaza-34,39-diphosphaoctacyclo[28.6.4.1~3,36~.1~28,31~.0~4,8~.0~7,12~.0~19,24~.0~23,27~]dotetraconta-5,7,9,11,15,19,21,23,25-nonaene 34,39-dioxide (non-preferred name)


Mass: 746.600 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26F2N10O8P2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 130 / 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: 2.02 Å3/Da / Density % sol: 39.14 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1M HEPES pH 7.5, 0.2M CaCl2, 15% (w/v) PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97852 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 2.38→50 Å / Num. obs: 14725 / % possible obs: 100 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.075 / Net I/σ(I): 24.79
Reflection shellResolution: 2.38→2.47 Å / Rmerge(I) obs: 0.235 / Num. unique obs: 1428

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
HKL-3000data scaling
PHASERphasing
Cootmodel building
HKL-3000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4F9E

4f9e


Resolution: 2.38→30.46 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.876 / SU B: 9.043 / SU ML: 0.213 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.757 / ESU R Free: 0.299 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2605 689 4.7 %RANDOM
Rwork0.2084 ---
obs0.2108 14036 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 72.38 Å2 / Biso mean: 23.885 Å2 / Biso min: 7.59 Å2
Baniso -1Baniso -2Baniso -3
1--0.9 Å2-0 Å2-0 Å2
2---0.21 Å20 Å2
3---1.12 Å2
Refinement stepCycle: final / Resolution: 2.38→30.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2826 0 96 130 3052
Biso mean--13.5 26.41 -
Num. residues----349
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0133103
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172823
X-RAY DIFFRACTIONr_angle_refined_deg1.261.7044226
X-RAY DIFFRACTIONr_angle_other_deg1.1461.5996532
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.145363
X-RAY DIFFRACTIONr_dihedral_angle_2_deg25.26320.348201
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.15615528
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.4971539
X-RAY DIFFRACTIONr_chiral_restr0.0530.2389
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023482
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02715
Refine LS restraints NCS

Ens-ID: 1 / Number: 5239 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.11 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.38→2.442 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.418 55 -
Rwork0.241 1010 -
all-1065 -
obs--98.61 %

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