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- PDB-9lio: Human cGAS catalytic domain bound with XL-3123 -

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Basic information

Entry
Database: PDB / ID: 9lio
TitleHuman cGAS catalytic domain bound with XL-3123
ComponentsCyclic GMP-AMP synthase
KeywordsIMMUNE SYSTEM / cGAS / inhibitor
Function / homology
Function and homology information


2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / 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 / regulation of T cell activation / pattern recognition receptor signaling pathway / cGMP-mediated signaling ...2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / 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 / regulation of T cell activation / pattern recognition receptor signaling pathway / cGMP-mediated signaling / cytoplasmic pattern recognition receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / cellular response to exogenous dsRNA / positive regulation of type I interferon production / negative regulation of double-strand break repair via homologous recombination / cAMP-mediated signaling / nucleosome binding / positive regulation of defense response to virus by host / phosphatidylinositol-4,5-bisphosphate binding / activation of innate immune response / 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 / nucleoplasm / ATP binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Mab-21-like, nucleotidyltransferase domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21
Similarity search - Domain/homology
: / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsZhao, W.F. / Li, M.J. / Xu, Y.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Discovery of novel cGAS inhibitors
Authors: Zhao, W.F. / Xu, Y.C.
History
DepositionJan 14, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 4, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)86,9836
Polymers85,5192
Non-polymers1,4644
Water3,045169
1
A: Cyclic GMP-AMP synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4913
Polymers42,7591
Non-polymers7322
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cyclic GMP-AMP synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4913
Polymers42,7591
Non-polymers7322
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)210.478, 45.949, 86.381
Angle α, β, γ (deg.)90.00, 112.68, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Cyclic GMP-AMP synthase / cGAMP synthase / cGAS / 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-A1EKD / 2-[bis[1-[4,6-bis(fluoranyl)-1,3-benzothiazol-2-yl]-3-methyl-5-oxidanyl-pyrazol-4-yl]methyl]benzoic acid


Mass: 666.625 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H18F4N6O4S2 / 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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 169 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.25 Å3/Da / Density % sol: 45.41 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 18-20% V/V PEG 3350, 0.2 M AMMONIUM CITRATE

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 23, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.92→97.1 Å / Num. obs: 58969 / % possible obs: 100 % / Redundancy: 6.6 % / CC1/2: 0.997 / Rmerge(I) obs: 0.114 / Rpim(I) all: 0.048 / Rrim(I) all: 0.123 / Χ2: 0.81 / Net I/σ(I): 6.2 / Num. measured all: 389171
Reflection shellResolution: 1.92→2.02 Å / % possible obs: 100 % / Redundancy: 5.8 % / Rmerge(I) obs: 1.835 / Num. measured all: 49744 / Num. unique obs: 8508 / CC1/2: 0.429 / Rpim(I) all: 0.833 / Rrim(I) all: 2.02 / Χ2: 0.95 / Net I/σ(I) obs: 0.9

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.92→78.12 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 31.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2682 2932 4.99 %
Rwork0.2238 --
obs0.2261 58742 99.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.92→78.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5508 0 94 169 5771
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095712
X-RAY DIFFRACTIONf_angle_d1.1277684
X-RAY DIFFRACTIONf_dihedral_angle_d7.797735
X-RAY DIFFRACTIONf_chiral_restr0.058838
X-RAY DIFFRACTIONf_plane_restr0.011960
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.92-1.950.41231090.41372524X-RAY DIFFRACTION96
1.95-1.980.45851600.37542562X-RAY DIFFRACTION98
1.98-2.020.35481370.34112649X-RAY DIFFRACTION100
2.02-2.060.35351430.32062639X-RAY DIFFRACTION100
2.06-2.10.34991290.29152675X-RAY DIFFRACTION100
2.1-2.150.33791370.28392618X-RAY DIFFRACTION100
2.15-2.20.33941340.26572698X-RAY DIFFRACTION100
2.2-2.250.3181160.24232643X-RAY DIFFRACTION100
2.25-2.310.30851430.24252650X-RAY DIFFRACTION100
2.31-2.380.24771290.23552646X-RAY DIFFRACTION100
2.38-2.460.30341370.23852660X-RAY DIFFRACTION100
2.46-2.540.3031650.22792643X-RAY DIFFRACTION100
2.54-2.650.33511320.23282658X-RAY DIFFRACTION100
2.65-2.770.27561340.22562680X-RAY DIFFRACTION100
2.77-2.910.27141560.23142655X-RAY DIFFRACTION100
2.91-3.090.28611380.23762657X-RAY DIFFRACTION100
3.09-3.330.28381490.22572681X-RAY DIFFRACTION100
3.33-3.670.25991320.20652680X-RAY DIFFRACTION100
3.67-4.20.26161550.19252701X-RAY DIFFRACTION100
4.2-5.290.22051520.18132700X-RAY DIFFRACTION100
5.29-78.120.20031450.20352791X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: -36.0571 Å / Origin y: 6.5425 Å / Origin z: 16.4843 Å
111213212223313233
T0.3118 Å20.0008 Å2-0.0645 Å2-0.1919 Å2-0.0041 Å2--0.2651 Å2
L1.2628 °20.3938 °2-0.4982 °2-0.6238 °2-0.348 °2--1.0927 °2
S0.035 Å °-0.243 Å °-0.0429 Å °0.1813 Å °-0.0866 Å °-0.1704 Å °-0.0248 Å °0.1771 Å °0.0545 Å °
Refinement TLS groupSelection details: all

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