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- PDB-6lrc: Human cGAS catalytic domain bound with the inhibitor PF-06928215 -

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Basic information

Entry
Database: PDB / ID: 6lrc
TitleHuman cGAS catalytic domain bound with the inhibitor PF-06928215
ComponentsCyclic GMP-AMP synthase
KeywordsDNA BINDING PROTEIN / cGAS / Inhibitor / Complex structure
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-KHM / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.831 Å
AuthorsZhao, W.F. / Xu, Y.C.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81620108027 China
National Natural Science Foundation of China (NSFC)21632008 China
CitationJournal: J.Chem.Inf.Model. / Year: 2020
Title: In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing.
Authors: Zhao, W. / Xiong, M. / Yuan, X. / Li, M. / Sun, H. / Xu, Y.
History
DepositionJan 15, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 24, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 11, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 13, 2021Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.3Nov 29, 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

Downloads & links

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Assembly

Deposited unit
B: Cyclic GMP-AMP synthase
A: Cyclic GMP-AMP synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,4106
Polymers85,5192
Non-polymers8924
Water6,197344
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)207.004, 45.652, 85.875
Angle α, β, γ (deg.)90.000, 111.560, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 42759.270 Da / Num. of mol.: 2
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) / References: UniProt: Q8N884, cyclic GMP-AMP synthase
#2: Chemical ChemComp-KHM / (1R,2S)-2-[(7-hydroxy-5-phenylpyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]cyclohexane-1-carboxylic acid


Mass: 380.397 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 344 / 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: 2.21 Å3/Da / Density % sol: 44.25 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 18-20% V/V PEG 3350, 0.2M AMMONIUM CITRATE (PH 7)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 3, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.78→50 Å / Num. obs: 71799 / % possible obs: 100 % / Redundancy: 6.4 % / Biso Wilson estimate: 18.86 Å2 / Rmerge(I) obs: 0.11 / Rpim(I) all: 0.047 / Rrim(I) all: 0.119 / Χ2: 0.944 / Net I/σ(I): 5.9 / Num. measured all: 456405
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.78-1.815.11.18135550.5820.5721.3170.892100
1.81-1.845.61.11935850.6430.5111.2340.901100
1.84-1.886.31.01135400.7250.4361.1030.898100
1.88-1.926.40.87635860.7760.3710.9530.926100
1.92-1.966.50.74135540.8350.3130.8060.933100
1.96-26.50.59235430.8770.2490.6430.959100
2-2.056.40.49435900.9140.210.5380.971100
2.05-2.116.30.39835590.9310.1710.4341.014100
2.11-2.1760.32435790.9480.1440.3551.007100
2.17-2.246.30.26635640.9660.1150.291.052100
2.24-2.326.80.24235670.9740.10.2621.057100
2.32-2.426.70.19635860.9810.0810.2121.043100
2.42-2.536.70.16735870.9820.0690.1811.056100
2.53-2.666.60.14635660.9830.0620.1591.025100
2.66-2.836.20.1236020.990.0520.1311.004100
2.83-3.046.70.136180.9910.0420.1090.966100
3.04-3.356.90.08235880.9930.0340.0880.898100
3.35-3.836.60.06836160.9940.0290.0730.831100
3.83-4.836.40.0636480.9950.0260.0650.745100
4.83-506.40.05837660.9950.0250.0640.69499.8

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.12_2829refinement
PDB_EXTRACT3.25data extraction
PHASER2.6.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LEV

4lev


Resolution: 1.831→36.86 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 21.39
RfactorNum. reflection% reflection
Rfree0.2189 3202 4.87 %
Rwork0.1861 --
obs0.1877 65729 99.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 71.24 Å2 / Biso mean: 25.0576 Å2 / Biso min: 9.02 Å2
Refinement stepCycle: final / Resolution: 1.831→36.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5600 0 58 344 6002
Biso mean--21.95 30.64 -
Num. residues----701
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075794
X-RAY DIFFRACTIONf_angle_d0.8597800
X-RAY DIFFRACTIONf_chiral_restr0.049862
X-RAY DIFFRACTIONf_plane_restr0.005984
X-RAY DIFFRACTIONf_dihedral_angle_d4.314919
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.8311-1.85840.31361120.2561233387
1.8584-1.88750.31071310.237262597
1.8875-1.91840.25971440.2233270199
1.9184-1.95150.27951300.21462711100
1.9515-1.9870.24221390.19992749100
1.987-2.02520.23391320.18442682100
2.0252-2.06650.25491310.1912755100
2.0665-2.11150.24891330.18292722100
2.1115-2.16060.20571110.18072775100
2.1606-2.21460.21141160.1792694100
2.2146-2.27450.23081420.17852762100
2.2745-2.34140.21841330.18552723100
2.3414-2.41690.24011320.18592744100
2.4169-2.50330.21791540.1872711100
2.5033-2.60350.22141390.18732736100
2.6035-2.7220.2321600.18732708100
2.722-2.86540.22111590.19572771100
2.8654-3.04490.23791530.18842728100
3.0449-3.27980.2171520.192730100
3.2798-3.60960.22291460.18152731100
3.6096-4.13140.20051490.16762795100
4.1314-5.20270.17611370.1632788100
5.2027-36.860.18721670.1954285399
Refinement TLS params.Method: refined / Origin x: 19.3808 Å / Origin y: -9.0803 Å / Origin z: 23.331 Å
111213212223313233
T0.1402 Å20.0089 Å2-0.019 Å2-0.099 Å2-0.0031 Å2--0.1423 Å2
L0.3289 °2-0.0966 °2-0.1768 °2-0.2537 °20.1035 °2--0.2882 °2
S0.0082 Å °0.0402 Å °0.0021 Å °-0.0699 Å °-0.0261 Å °0.0856 Å °-0.0177 Å °-0.0402 Å °0.0178 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allB161 - 520
2X-RAY DIFFRACTION1allA161 - 520
3X-RAY DIFFRACTION1allE1 - 2
4X-RAY DIFFRACTION1allS1 - 344
5X-RAY DIFFRACTION1allC1 - 2

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