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- PDB-6mjw: human cGAS catalytic domain bound with the inhibitor G150 -

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Basic information

Entry
Database: PDB / ID: 6mjw
Titlehuman cGAS catalytic domain bound with the inhibitor G150
ComponentsCyclic GMP-AMP synthase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / human cGAS / DNA sensor / inhibitor / IMMUNE SYSTEM / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / regulation of immunoglobulin production / cGAS/STING signaling pathway / pattern recognition receptor signaling pathway / regulation of T cell activation / cytoplasmic pattern recognition receptor signaling pathway ...cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / regulation of immunoglobulin production / cGAS/STING signaling pathway / pattern recognition receptor signaling pathway / regulation of T cell activation / cytoplasmic pattern recognition receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / cGMP-mediated signaling / cellular response to exogenous dsRNA / positive regulation of type I interferon production / negative regulation of double-strand break repair via homologous recombination / nucleosome binding / positive regulation of defense response to virus by host / phosphatidylinositol-4,5-bisphosphate binding / activation of innate immune response / cAMP-mediated signaling / molecular condensate scaffold activity / determination of adult lifespan / positive regulation of cellular senescence / site of double-strand break / double-stranded DNA binding / defense response to virus / nuclear body / DNA repair / innate immune response / DNA damage response / chromatin binding / GTP binding / protein homodimerization activity / DNA binding / nucleoplasm / ATP binding / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Beta Polymerase; domain 2 - #90 / Poly(a)-polymerase, middle domain - #40 / Poly(a)-polymerase, middle domain / Mab-21-like, nucleotidyltransferase domain / Mab-21-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21 / Beta Polymerase; domain 2 ...Beta Polymerase; domain 2 - #90 / Poly(a)-polymerase, middle domain - #40 / Poly(a)-polymerase, middle domain / Mab-21-like, nucleotidyltransferase domain / Mab-21-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21 / Beta Polymerase; domain 2 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-JUJ / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.405 Å
AuthorsLama, L. / Adura, C. / Xie, W. / Tomita, D. / Kamei, T. / Kuryavyi, V. / Gogakos, T. / Steinberg, J.I. / Miller, M. / Ramos-Espiritu, L. ...Lama, L. / Adura, C. / Xie, W. / Tomita, D. / Kamei, T. / Kuryavyi, V. / Gogakos, T. / Steinberg, J.I. / Miller, M. / Ramos-Espiritu, L. / Asano, Y. / Hashizume, S. / Aida, J. / Imaeda, T. / Okamoto, R. / Jennings, A.J. / Michinom, M. / Kuroita, T. / Stamford, A. / Gao, P. / Meinke, P. / Glickman, J.F. / Patel, D.J. / Tuschl, T.
CitationJournal: Nat Commun / Year: 2019
Title: Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression.
Authors: Lama, L. / Adura, C. / Xie, W. / Tomita, D. / Kamei, T. / Kuryavyi, V. / Gogakos, T. / Steinberg, J.I. / Miller, M. / Ramos-Espiritu, L. / Asano, Y. / Hashizume, S. / Aida, J. / Imaeda, T. / ...Authors: Lama, L. / Adura, C. / Xie, W. / Tomita, D. / Kamei, T. / Kuryavyi, V. / Gogakos, T. / Steinberg, J.I. / Miller, M. / Ramos-Espiritu, L. / Asano, Y. / Hashizume, S. / Aida, J. / Imaeda, T. / Okamoto, R. / Jennings, A.J. / Michino, M. / Kuroita, T. / Stamford, A. / Gao, P. / Meinke, P. / Glickman, J.F. / Patel, D.J. / Tuschl, T.
History
DepositionSep 23, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cyclic GMP-AMP synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9433
Polymers43,4861
Non-polymers4572
Water81145
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.531, 116.531, 60.037
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number172
Space group name H-MP64

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Components

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


Mass: 43486.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CGAS, C6orf150, MB21D1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q8N884, cyclic GMP-AMP synthase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-JUJ / 1-[9-(6-aminopyridin-3-yl)-6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethan-1-one


Mass: 391.251 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16Cl2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 54.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.064 M sodium citrate 7.0, 0.1 M HEPES, pH 7.0, 10% PEG5000MME

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.4→29.35 Å / Num. obs: 17953 / % possible obs: 98.4 % / Redundancy: 9 % / CC1/2: 0.997 / Rmerge(I) obs: 0.055 / Rpim(I) all: 0.018 / Rrim(I) all: 0.058 / Net I/σ(I): 26.3
Reflection shellResolution: 2.4→2.44 Å / Redundancy: 4.4 % / Mean I/σ(I) obs: 2.4 / Num. unique obs: 1719 / CC1/2: 0.81 / Rpim(I) all: 0.227 / Rrim(I) all: 0.572 / % possible all: 93.2

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementResolution: 2.405→29.347 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.85
RfactorNum. reflection% reflection
Rfree0.2572 1796 10 %
Rwork0.2128 --
obs0.2173 17953 98.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.405→29.347 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2703 0 27 45 2775
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042789
X-RAY DIFFRACTIONf_angle_d0.5463740
X-RAY DIFFRACTIONf_dihedral_angle_d16.9551695
X-RAY DIFFRACTIONf_chiral_restr0.039403
X-RAY DIFFRACTIONf_plane_restr0.004469
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4052-2.47020.35591360.30711194X-RAY DIFFRACTION94
2.4702-2.54280.32641330.26461204X-RAY DIFFRACTION98
2.5428-2.62490.31991360.25491250X-RAY DIFFRACTION98
2.6249-2.71860.28671420.23671226X-RAY DIFFRACTION99
2.7186-2.82740.30931400.22831253X-RAY DIFFRACTION99
2.8274-2.9560.30271320.2451216X-RAY DIFFRACTION98
2.956-3.11160.29841410.2431252X-RAY DIFFRACTION99
3.1116-3.30630.28451400.23681254X-RAY DIFFRACTION99
3.3063-3.56120.28781400.2151256X-RAY DIFFRACTION99
3.5612-3.91890.24011370.20341246X-RAY DIFFRACTION100
3.9189-4.48420.26381420.19021247X-RAY DIFFRACTION98
4.4842-5.6430.21771370.18771273X-RAY DIFFRACTION100
5.643-29.3490.20451400.19961286X-RAY DIFFRACTION98

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