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- PDB-9c8t: Crystal Structure of human cyclic GMP-AMP synthase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 9c8t
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with AMPPNP and compound 2
ComponentsCyclic GMP-AMP synthase
KeywordsTRANSFERASE / DNA sensor / Nucleotidyltransferase
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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-JUJ / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.47 Å
AuthorsWang, L. / Sietsema, D.
Funding support United States, 1items
OrganizationGrant numberCountry
Other privateVentus therapeutics United States
CitationJournal: Commun Chem / Year: 2025
Title: Structural insight into the cGAS active site explains differences between therapeutically relevant species.
Authors: Skeldon, A.M. / Wang, L. / Sgarioto, N. / Beveridge, R.E. / Chan, S. / Dorich, S. / Dumais, V. / Fradet, N. / Gaudreault, S. / LeGros, P. / McKay, D. / Seliniotakis, R. / Sietsema, D.V. / ...Authors: Skeldon, A.M. / Wang, L. / Sgarioto, N. / Beveridge, R.E. / Chan, S. / Dorich, S. / Dumais, V. / Fradet, N. / Gaudreault, S. / LeGros, P. / McKay, D. / Seliniotakis, R. / Sietsema, D.V. / Zhang, L. / Boily, M.O. / Burch, J.D. / Caron, A. / Fader, L.D. / Lama, L. / Xie, W. / Patel, D.J. / Tuschl, T. / Crackower, M.A. / Pike, K.A.
History
DepositionJun 12, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release

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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)43,9507
Polymers42,8461
Non-polymers1,1046
Water5,405300
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)126.426, 51.972, 59.777
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 42846.277 Da / Num. of mol.: 1 / Mutation: K427E
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

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Non-polymers , 6 types, 306 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: 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
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 300 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.29 Å3/Da / Density % sol: 46.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1M Tris pH 8.0, 0.1 M Lithium Sulfate, 20% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.97 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 11, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.47→63.21 Å / Num. obs: 67719 / % possible obs: 100 % / Redundancy: 7.1 % / CC1/2: 0.999 / Net I/σ(I): 14.9
Reflection shellResolution: 1.471→1.496 Å / Redundancy: 6.3 % / Num. unique obs: 3349 / CC1/2: 0.537 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
HKL-2000data reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.47→63.21 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2121 3304 4.88 %
Rwork0.1864 --
obs0.1877 67708 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.47→63.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2788 0 66 300 3154
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0142948
X-RAY DIFFRACTIONf_angle_d1.3393972
X-RAY DIFFRACTIONf_dihedral_angle_d16.9751114
X-RAY DIFFRACTIONf_chiral_restr0.105433
X-RAY DIFFRACTIONf_plane_restr0.01491
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.47-1.490.27251420.25462642X-RAY DIFFRACTION100
1.49-1.510.28541240.24642643X-RAY DIFFRACTION100
1.51-1.540.28711480.23812664X-RAY DIFFRACTION100
1.54-1.560.24231390.21772609X-RAY DIFFRACTION100
1.56-1.590.25551300.20762667X-RAY DIFFRACTION100
1.59-1.620.24421330.20772675X-RAY DIFFRACTION100
1.62-1.650.23091300.19832652X-RAY DIFFRACTION100
1.65-1.680.21281250.19992658X-RAY DIFFRACTION100
1.68-1.720.20641360.19882653X-RAY DIFFRACTION100
1.72-1.760.20571480.19172676X-RAY DIFFRACTION100
1.76-1.80.23141350.1882630X-RAY DIFFRACTION100
1.8-1.850.22181430.18812664X-RAY DIFFRACTION100
1.85-1.910.21191230.18962657X-RAY DIFFRACTION100
1.91-1.970.21091320.19022680X-RAY DIFFRACTION100
1.97-2.040.25151440.18432683X-RAY DIFFRACTION100
2.04-2.120.19241260.18262672X-RAY DIFFRACTION100
2.12-2.220.2021480.1822690X-RAY DIFFRACTION100
2.22-2.330.20811350.18422688X-RAY DIFFRACTION100
2.33-2.480.24981390.18442709X-RAY DIFFRACTION100
2.48-2.670.22931430.19522673X-RAY DIFFRACTION100
2.67-2.940.23671420.18712710X-RAY DIFFRACTION100
2.94-3.370.18361480.18372733X-RAY DIFFRACTION100
3.37-4.240.17551420.16482777X-RAY DIFFRACTION100
4.24-63.210.20911490.18322899X-RAY DIFFRACTION100

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