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- PDB-5xze: Mouse cGAS bound to the inhibitor RU332 -

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Basic information

Entry
Database: PDB / ID: 5xze
TitleMouse cGAS bound to the inhibitor RU332
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-AE7 / DNA / DNA (> 10) / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.177 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.
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 1.0Oct 11, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_residues
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)51,8175
Polymers51,3863
Non-polymers4312
Water1,47782
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2710 Å2
ΔGint-18 kcal/mol
Surface area22100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.285, 98.633, 129.175
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-728-

HOH

21A-751-

HOH

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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: 42512.121 Da / Num. of mol.: 1 / Fragment: UNP residues 147-505
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, 84 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-AE7 / (3R)-3-[1-(3H-1lambda~4~,3-benzothiazol-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]-2-benzofuran-1(3H)-one


Mass: 365.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15N3O3S
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / 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: 2.67 Å3/Da / Density % sol: 53.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M MES, pH 6.3, 25% PEG400, 0.1 M magnesium chloride

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 27, 2015
RadiationMonochromator: Cryogenically-cooled single crystal Si(220) side bounce
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.177→50 Å / Num. obs: 28373 / % possible obs: 98.09 % / Redundancy: 3.6 % / Net I/σ(I): 12.8
Reflection shellHighest resolution: 2.177 Å

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.177→39.197 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 35.91
RfactorNum. reflection% reflection
Rfree0.2807 1428 5.03 %
Rwork0.2422 --
obs0.2442 28373 98.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 184.38 Å2 / Biso mean: 67.45 Å2 / Biso min: 29.62 Å2
Refinement stepCycle: final / Resolution: 2.177→39.197 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2937 592 26 82 3637
Biso mean--86.72 53.97 -
Num. residues----386
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0093694
X-RAY DIFFRACTIONf_angle_d1.2535095
X-RAY DIFFRACTIONf_chiral_restr0.048549
X-RAY DIFFRACTIONf_plane_restr0.005545
X-RAY DIFFRACTIONf_dihedral_angle_d20.461466
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1767-2.25440.40871400.38992496263693
2.2544-2.34470.39871330.3512692282599
2.3447-2.45140.38631480.33382692284099
2.4514-2.58060.34561430.309727092852100
2.5806-2.74230.32951500.301527092859100
2.7423-2.95390.34351280.298127402868100
2.9539-3.25110.30971440.27582718286299
3.2511-3.72120.27491400.2362743288399
3.7212-4.68710.22361580.19632716287498
4.6871-39.20290.24471440.19092730287494
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)
13.2589-0.1160.4713.0136-0.24342.43250.05290.46850.4596-0.4954-0.0144-0.0547-0.21430.0962-0.01560.3921-0.07960.04070.40.1070.5271101.3108211.8781293.1301
21.61380.5403-0.22353.3866-1.09072.0160.04230.3489-0.0231-0.5182-0.1668-0.4167-0.09840.39480.09810.4274-0.00650.07190.44630.01620.5192106.7151204.052289.2943
32.5287-0.11060.19542.37871.34632.13690.1066-0.37020.2270.10240.1154-0.6987-0.08510.5166-0.18480.3024-0.06-0.01650.42820.02430.5869107.6158206.1474313.6681
47.55093.81420.35296.7807-2.76998.94580.16651.4387-0.2928-0.67280.254-0.7273-0.1667-0.3189-0.4151.4161-0.14020.17741.75960.00730.965483.8626213.9607279.4493
56.93081.1259-0.84127.93681.32443.75190.203-0.16541.16560.45430.09990.452-0.8536-0.2994-0.19660.53670.02110.10630.30720.02350.619483.6077218.8008304.6611
65.11660.40390.30695.52930.98855.91110.1525-0.12370.2043-0.0670.16480.33180.0864-1.5974-0.32120.56180.0119-0.04110.70240.10510.647882.1032215.6923298.0468
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 149 through 234 )A149 - 234
2X-RAY DIFFRACTION2chain 'A' and (resid 235 through 376 )A235 - 376
3X-RAY DIFFRACTION3chain 'A' and (resid 377 through 505 )A377 - 505
4X-RAY DIFFRACTION4chain 'E' and (resid 1 through 5 )E1 - 5
5X-RAY DIFFRACTION5chain 'E' and (resid 6 through 15 )E6 - 15
6X-RAY DIFFRACTION6chain 'F' and (resid 4 through 17 )F4 - 17

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