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- PDB-9mdc: Crystal Structure of human cyclic GMP-AMP synthase (cGAS) in comp... -

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Basic information

Entry
Database: PDB / ID: 9mdc
TitleCrystal Structure of human cyclic GMP-AMP synthase (cGAS) in complex with compound 36; (S)-(6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(5-(2-hydroxyethoxy)pyrimidin-2-yl)methanone
ComponentsCyclic GMP-AMP synthase
KeywordsTRANSFERASE / human cyclic GMP-AMP synthase AMP-PNP Compound 36
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 / : ...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 / : / 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 / : / 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 / cytoplasm / cytosol
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 / : / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.25 Å
AuthorsSietsema, D.V.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization.
Authors: Cyr, P. / Fader, L.D. / Burch, J.D. / Pike, K.A. / Sietsema, D.V. / Boily, M.O. / Ciblat, S. / Sgarioto, N. / Skeldon, A.M. / Gaudreault, S. / Le Gros, P. / Dumais, V. / McKay, D.J.J. / ...Authors: Cyr, P. / Fader, L.D. / Burch, J.D. / Pike, K.A. / Sietsema, D.V. / Boily, M.O. / Ciblat, S. / Sgarioto, N. / Skeldon, A.M. / Gaudreault, S. / Le Gros, P. / Dumais, V. / McKay, D.J.J. / Abraham, N.S. / Seliniotakis, R. / Beveridge, R.E.
History
DepositionDec 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9036
Polymers42,8001
Non-polymers1,1035
Water2,720151
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)129.030, 51.120, 60.190
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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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: 42800.168 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) / References: UniProt: Q8N884, cyclic GMP-AMP synthase

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Non-polymers , 5 types, 156 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-A1BJA / [(1S)-6,7-dichloro-1-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl][5-(2-hydroxyethoxy)pyrimidin-2-yl]methanone


Mass: 421.277 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18Cl2N4O3
#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-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 151 / 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: 2.41 Å3/Da / Density % sol: 49 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: (5mg/ml) HcGAS catalytic domain was mixed with 17/16 bp dsDNA in a molar ratio of 1:1.25 protein:DNA in a buffer containing 20 mM Tris pH 7.5, 150 mM NaCl, 10mM MnCl2, 1mM TCEP, 5mM AMPPNP ...Details: (5mg/ml) HcGAS catalytic domain was mixed with 17/16 bp dsDNA in a molar ratio of 1:1.25 protein:DNA in a buffer containing 20 mM Tris pH 7.5, 150 mM NaCl, 10mM MnCl2, 1mM TCEP, 5mM AMPPNP and 1mM compound. Crystals were obtained with sitting drop vapor diffusion in drops mixed 1:1 with a reservoir of 0.1M Tris pH 8.0, 0.1 M Lithium Sulfate, 20% PEG 4000 and cGAS crystal seeds. Crystals were cryo-protected using reservoir solution supplemented with 25% ethylene glycol and flash-frozen in Liquid N2.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.953 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Mar 22, 2024
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.953 Å / Relative weight: 1
ReflectionResolution: 1.25→47.53 Å / Num. obs: 110154 / % possible obs: 99.9 % / Redundancy: 2 % / Biso Wilson estimate: 17.4 Å2 / CC1/2: 0.999 / Net I/σ(I): 9.71
Reflection shellResolution: 1.25→1.295 Å / Rmerge(I) obs: 0.02888 / Num. unique obs: 110154 / CC1/2: 0.999 / Rpim(I) all: 0.02888 / Rrim(I) all: 0.04085

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.25→47.53 Å / SU ML: 0.1738 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.3193
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2028 5541 5.03 %
Rwork0.176 104602 -
obs0.1773 110143 99.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.2 Å2
Refinement stepCycle: LAST / Resolution: 1.25→47.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2912 0 62 151 3125
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00513188
X-RAY DIFFRACTIONf_angle_d0.79364309
X-RAY DIFFRACTIONf_chiral_restr0.0729453
X-RAY DIFFRACTIONf_plane_restr0.0083552
X-RAY DIFFRACTIONf_dihedral_angle_d17.7141258
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.25-1.260.40721650.37673383X-RAY DIFFRACTION99.05
1.26-1.280.37281950.34943415X-RAY DIFFRACTION97.65
1.28-1.290.32471650.31223428X-RAY DIFFRACTION99.45
1.29-1.310.321900.30563406X-RAY DIFFRACTION97.93
1.31-1.330.30591780.2863432X-RAY DIFFRACTION99.61
1.33-1.350.3331750.27173426X-RAY DIFFRACTION98.15
1.35-1.370.2811770.26093448X-RAY DIFFRACTION99.72
1.37-1.390.26781670.25183441X-RAY DIFFRACTION98.5
1.39-1.410.25371910.22823442X-RAY DIFFRACTION99.7
1.41-1.430.23111880.21143458X-RAY DIFFRACTION98.86
1.43-1.460.22051840.20033445X-RAY DIFFRACTION99.53
1.46-1.480.21731950.193438X-RAY DIFFRACTION99.43
1.48-1.510.20331890.18823471X-RAY DIFFRACTION99.16
1.51-1.540.22341730.17463488X-RAY DIFFRACTION99.92
1.54-1.570.19631780.16833438X-RAY DIFFRACTION99.5
1.57-1.610.18361850.15293485X-RAY DIFFRACTION99.48
1.61-1.650.23021660.1473495X-RAY DIFFRACTION99.7
1.65-1.70.18341900.14673497X-RAY DIFFRACTION100
1.7-1.750.17261720.14713490X-RAY DIFFRACTION99.81
1.75-1.80.19182150.14813464X-RAY DIFFRACTION99.92
1.8-1.870.18931860.14433499X-RAY DIFFRACTION99.95
1.87-1.940.16231920.15043513X-RAY DIFFRACTION99.97
1.94-2.030.18542070.1593485X-RAY DIFFRACTION100
2.03-2.140.17431840.15473549X-RAY DIFFRACTION99.97
2.14-2.270.19211770.15443511X-RAY DIFFRACTION100
2.27-2.450.19771890.1633550X-RAY DIFFRACTION100
2.45-2.690.19692130.17023530X-RAY DIFFRACTION99.89
2.69-3.080.20271810.18013579X-RAY DIFFRACTION99.79
3.08-3.880.19931910.17623609X-RAY DIFFRACTION99.82
3.88-47.530.19771830.17693787X-RAY DIFFRACTION99.18

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