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- PDB-5xzb: Mouse cGAS bound to the inhibitor RU365 -

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Basic information

Entry
Database: PDB / ID: 5xzb
TitleMouse cGAS bound to the inhibitor RU365
Components
  • Cyclic GMP-AMP synthase
  • DNA (5'-D(*AP*AP*AP*TP*TP*GP*CP*CP*GP*AP*AP*GP*AP*CP*G)-3')
  • DNA (5'-D(P*CP*GP*TP*CP*TP*TP*CP*GP*GP*CP*AP*AP*TP*T)-3')
KeywordsIMMUNE SYSTEM/INHIBITOR / Inhibitor / cGAS / STING / IMMUNE SYSTEM-INHIBITOR complex
Function / homology
Function and homology information


2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / regulation of type I interferon production / regulation of immunoglobulin production / cGAS/STING signaling pathway / regulation of T cell activation / negative regulation of cGAS/STING signaling pathway / negative regulation of DNA repair ...2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / regulation of type I interferon production / regulation of immunoglobulin production / cGAS/STING signaling pathway / regulation of T cell activation / negative regulation of cGAS/STING signaling pathway / negative regulation of DNA repair / cGMP-mediated signaling / cellular response to exogenous dsRNA / positive regulation of type I interferon production / nucleosome binding / regulation of immune response / negative regulation of double-strand break repair via homologous recombination / positive regulation of defense response to virus by host / activation of innate immune response / phosphatidylinositol-4,5-bisphosphate binding / cAMP-mediated signaling / determination of adult lifespan / molecular condensate scaffold activity / positive regulation of cellular senescence / site of double-strand break / double-stranded DNA binding / defense response to virus / nuclear body / innate immune response / DNA repair / DNA damage response / chromatin binding / GTP binding / protein homodimerization activity / DNA binding / ATP binding / nucleus / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Beta Polymerase; domain 2 - #90 / Poly(a)-polymerase, middle domain - #40 / Mab-21-like, nucleotidyltransferase domain / Mab-21-like / Mab-21-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 / Mab-21 protein nucleotidyltransferase domain / Poly(a)-polymerase, middle domain / Beta Polymerase; domain 2 ...Beta Polymerase; domain 2 - #90 / Poly(a)-polymerase, middle domain - #40 / Mab-21-like, nucleotidyltransferase domain / Mab-21-like / Mab-21-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 / Mab-21 protein nucleotidyltransferase domain / Poly(a)-polymerase, middle domain / Beta Polymerase; domain 2 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-A9Y / DNA / DNA (> 10) / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.13 Å
AuthorsVincent, J. / Adura, C. / Gao, P. / Luz, A. / Lama, L. / Asano, Y. / Okamoto, R. / Imaeda, T. / Aida, J. / Rothamel, K. ...Vincent, J. / Adura, C. / Gao, P. / Luz, A. / Lama, L. / Asano, Y. / Okamoto, R. / Imaeda, T. / Aida, J. / Rothamel, K. / Gogakos, T. / Steinberg, J. / Reasoner, S. / Aso, K. / Tuschl, T. / Patel, D.J. / Glickman, J.F. / Ascano, M.
Funding support China, United States, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)NSFC31670903 China
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM104962 United States
CitationJournal: Nat Commun / Year: 2017
Title: Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice.
Authors: Vincent, J. / Adura, C. / Gao, P. / Luz, A. / Lama, L. / Asano, Y. / Okamoto, R. / Imaeda, T. / Aida, J. / Rothamel, K. / Gogakos, T. / Steinberg, J. / Reasoner, S. / Aso, K. / Tuschl, T. / ...Authors: Vincent, J. / Adura, C. / Gao, P. / Luz, A. / Lama, L. / Asano, Y. / Okamoto, R. / Imaeda, T. / Aida, J. / Rothamel, K. / Gogakos, T. / Steinberg, J. / Reasoner, S. / Aso, K. / Tuschl, T. / Patel, D.J. / Glickman, J.F. / Ascano, M.
History
DepositionJul 12, 2017Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Aug 9, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 12, 2022Group: Database references / Other / Category: database_2 / pdbx_database_status
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.deposit_site
Revision 1.5May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclic GMP-AMP synthase
E: DNA (5'-D(*AP*AP*AP*TP*TP*GP*CP*CP*GP*AP*AP*GP*AP*CP*G)-3')
F: DNA (5'-D(P*CP*GP*TP*CP*TP*TP*CP*GP*GP*CP*AP*AP*TP*T)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,2565
Polymers50,8443
Non-polymers4122
Water1,18966
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2720 Å2
ΔGint-17 kcal/mol
Surface area21780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.502, 98.841, 130.201
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Cyclic GMP-AMP synthase / m-cGAS / 2'3'-cGAMP synthase / Mab-21 domain-containing protein 1


Mass: 41970.508 Da / Num. of mol.: 1 / Fragment: UNP residues 149-505
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Mb21d1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q8C6L5, cyclic GMP-AMP synthase

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DNA chain , 2 types, 2 molecules EF

#2: DNA chain DNA (5'-D(*AP*AP*AP*TP*TP*GP*CP*CP*GP*AP*AP*GP*AP*CP*G)-3')


Mass: 4627.037 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Mus musculus (house mouse)
#3: DNA chain DNA (5'-D(P*CP*GP*TP*CP*TP*TP*CP*GP*GP*CP*AP*AP*TP*T)-3')


Mass: 4246.764 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Mus musculus (house mouse)

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Non-polymers , 3 types, 68 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-A9Y / (3R)-3-[1-(1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]-2-benzofuran-1(3H)-one


Mass: 346.339 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H14N4O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 66 / Source method: isolated from a natural source / Formula: H2O

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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: 2.71 Å3/Da / Density % sol: 54.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M MES, pH 6.3, 26% PEG400, 0.1 M magnesium chloride

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 1.008 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Aug 18, 2015
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.008 Å / Relative weight: 1
ReflectionResolution: 2.13→78.726 Å / Num. obs: 30303 / % possible obs: 97.04 % / Redundancy: 3.2 % / Net I/σ(I): 13.3
Reflection shellHighest resolution: 2.13 Å

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
PHASERphasing
PDB_EXTRACT3.22data extraction
XDSdata reduction
XDSdata scaling
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.13→78.726 Å / FOM work R set: 0.7688 / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.76 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2475 1530 5.05 %
Rwork0.2132 28773 -
obs0.2149 30303 97.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 187.64 Å2 / Biso mean: 72.74 Å2 / Biso min: 33.46 Å2
Refinement stepCycle: final / Resolution: 2.13→78.726 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2937 592 27 66 3622
Biso mean--152.46 56.46 -
Num. residues----386
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0093694
X-RAY DIFFRACTIONf_angle_d1.2285095
X-RAY DIFFRACTIONf_chiral_restr0.045549
X-RAY DIFFRACTIONf_plane_restr0.005545
X-RAY DIFFRACTIONf_dihedral_angle_d20.4891466
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1301-2.19890.42141380.38432603274197
2.1989-2.27740.44491380.40032399253792
2.2774-2.36860.41291350.33392596273196
2.3686-2.47640.31451310.28922624275599
2.4764-2.6070.2931180.258926842802100
2.607-2.77040.3041670.260326482815100
2.7704-2.98430.31151430.26722639278298
2.9843-3.28460.27561430.24552663280699
3.2846-3.75990.24741200.21052633275397
3.7599-4.7370.18961600.16592616277696
4.737-78.77980.1931370.16162668280593
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.5163-0.41420.57892.76380.30586.22660.0290.00060.6961-0.1311-0.02660.1236-0.6314-0.22670.11890.3518-0.07470.01760.40920.03120.802498.1074122.9176170.2856
23.2192-0.965-0.50555.03355.4092.5653-0.11090.26780.2561-0.566-0.28170.1354-0.57720.17270.4590.5962-0.04540.0250.40540.12330.5691100.5113.0446162.3714
36.6119-1.7415-2.18248.56290.11354.6356-0.1080.1957-0.9251-0.7051-0.0493-0.45990.95450.5977-0.13380.52780.08410.09570.5614-0.0470.734111.797792.9795159.4773
43.13783.2523-1.3117.6015-1.29616.9938-0.0381.4227-0.9696-2.06150.1234-0.04390.30910.5884-0.00740.96360.12220.15910.9706-0.0830.7005110.292197.4793146.7264
51.64191.0627-0.78473.9801-1.76533.04720.02380.25030.1527-0.3671-0.1368-0.2717-0.13780.30590.11260.36390.01430.02510.43770.04140.4949104.9441108.8533163.19
64.63141.0756-2.51893.89630.07896.0284-0.021-0.3739-0.1012-0.2994-0.154-0.8850.02381.06750.15170.41880.00780.0260.45760.10160.6481110.0383102.6869166.4395
72.89580.23410.33223.55581.65262.54070.1026-0.42560.1580.10810.1141-0.6278-0.10040.526-0.19190.3811-0.0606-0.03160.50060.02330.5484107.8381107.7573185.9576
83.44910.80840.22787.2562-1.92295.24810.28270.87770.6149-1.12220.1496-0.5216-0.7314-0.119-0.34460.67790.07470.18590.6330.03840.717383.9143118.8157168.8152
92.58650.4901-0.84665.29514.49612.22770.02310.18230.0571-0.0975-0.11850.62390.3064-2.1553-0.39320.888-0.0321-0.0350.96360.09390.784982.2358117.2926170.363
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 149 through 183 )A149 - 183
2X-RAY DIFFRACTION2chain 'A' and (resid 184 through 219 )A184 - 219
3X-RAY DIFFRACTION3chain 'A' and (resid 220 through 239 )A220 - 239
4X-RAY DIFFRACTION4chain 'A' and (resid 240 through 258 )A240 - 258
5X-RAY DIFFRACTION5chain 'A' and (resid 259 through 348 )A259 - 348
6X-RAY DIFFRACTION6chain 'A' and (resid 349 through 376 )A349 - 376
7X-RAY DIFFRACTION7chain 'A' and (resid 377 through 505 )A377 - 505
8X-RAY DIFFRACTION8chain 'E' and (resid 1 through 15 )E1 - 15
9X-RAY DIFFRACTION9chain 'F' and (resid 4 through 17 )F4 - 17

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