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- PDB-7fup: Crystal Structure of human cyclic GMP-AMP synthase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 7fup
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with methyl 1-benzoyl-3-methyl-5-(1,2-oxazol-5-yl)pyrazole-4-carboxylate
ComponentsCyclic GMP-AMP synthase
KeywordsTRANSFERASE / IMMUNE RESPONSE / NTASE / DNA SENSOR
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 / 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
PROPANOIC ACID / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.411 Å
AuthorsLeibrock, L. / Benz, J. / Groebke-Zbinden, K. / Rudolph, M.G.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
F. Hoffmann-La Roche LTD Switzerland
CitationJournal: To be published
Title: Crystal Structure of a human cyclic GMP-AMP synthase complex
Authors: Groebke-Zbinden, K. / Vandemeulebroucke, A. / Hilbert, M. / Rudolph, M.G.
History
DepositionFeb 8, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 21, 2024Provider: 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)42,7504
Polymers42,5361
Non-polymers2143
Water90150
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, elutes as a monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)102.353, 102.353, 242.377
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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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: 42536.102 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 161-522
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CGAS, C6orf150, MB21D1 / Plasmid: pET21a_cGAS(161-522_wt) / Production host: Escherichia coli (E. coli) / 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-PPI / PROPANOIC ACID


Mass: 74.079 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / 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: 4.32 Å3/Da / Density % sol: 71.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 10-12 mg/mL protein in 25 mM Tris/HCl pH7.5, 500mM NaCl, 2mM TCEP, supplemented with 10x molar excess of ligand and, if needed, with 10 mM MgCl2 and 5mM ATP, then mixed 1:1 with reservoir of ...Details: 10-12 mg/mL protein in 25 mM Tris/HCl pH7.5, 500mM NaCl, 2mM TCEP, supplemented with 10x molar excess of ligand and, if needed, with 10 mM MgCl2 and 5mM ATP, then mixed 1:1 with reservoir of the Procomplex screen. Several conditions resulted in crystals.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00006 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jul 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00006 Å / Relative weight: 1
ReflectionResolution: 2.41→83.25 Å / Num. obs: 29746 / % possible obs: 99.3 % / Redundancy: 19.329 % / Biso Wilson estimate: 76.801 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.205 / Rrim(I) all: 0.211 / Χ2: 0.759 / Net I/σ(I): 12.87 / Num. measured all: 574971 / Scaling rejects: 174
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible allCC1/2
2.41-2.4717.6289.90.16363852153206410.44495.9
2.47-2.5420.3876.9990.3942792211820997.17399.10.199
2.54-2.6220.4965.2330.6341688205220345.36499.10.31
2.62-2.720.1273.990.8640012200319884.09199.30.477
2.7-2.7819.9033.0611.237835191119013.1499.50.532
2.78-2.8818.8062.0831.7335280188518762.1499.50.716
2.88-2.9920.0471.4882.5935945180217931.52699.50.859
2.99-3.1120.4161.0133.8836035177217651.03999.60.934
3.11-3.2520.0540.6695.6933169165916540.68699.70.964
3.25-3.4119.4520.4448.1431784164016340.45599.60.981
3.41-3.5918.4270.26712.2427954152115170.27599.70.992
3.59-3.8120.0860.19517.6129527147514700.299.70.996
3.81-4.0819.7080.14422.4127178138013790.14899.90.997
4.08-4.419.2270.09630.8124976129912990.0991000.999
4.4-4.8218.1040.07835.5821743120112010.081000.999
4.82-5.3919.5520.07837.5321703111211100.0899.80.999
5.39-6.2318.730.08334.45182629769750.08599.90.999
6.23-7.6217.1160.06540.26146008538530.0671000.999
7.62-10.7817.3290.03661.7119926936920.03799.91
10.78-50.07313.8260.02964.4261114454420.0399.31

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.16rc1_3531refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.411→50.073 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.86 / Stereochemistry target values: ML
Details: methyl 1-benzoyl-3-methyl-5-(1,2-oxazol-5-yl)pyrazole-4-carboxylate soak lead to chemical modification of cGAS. Cys199 is modified, possibly with benzoyl group. Lys439 is modified, possibly ...Details: methyl 1-benzoyl-3-methyl-5-(1,2-oxazol-5-yl)pyrazole-4-carboxylate soak lead to chemical modification of cGAS. Cys199 is modified, possibly with benzoyl group. Lys439 is modified, possibly with propionyl group. Electron density emanating from both residues was modeled by propionyl groups, but origin unclear.
RfactorNum. reflection% reflectionSelection details
Rfree0.2267 994 5.01 %RANDOM
Rwork0.1785 18832 --
obs0.1809 19826 66.41 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 181.08 Å2 / Biso mean: 65.8163 Å2 / Biso min: 21.15 Å2
Refinement stepCycle: final / Resolution: 2.411→50.073 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2931 0 9 50 2990
Biso mean--54.46 51.5 -
Num. residues----357
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4111-2.53830.5176190.383638340210
2.5383-2.69730.3928310.315179983020
2.6973-2.90550.4047790.27921504158338
2.9055-3.19790.30092060.24393697390393
3.1979-3.66050.23852100.193440304240100
3.6605-4.61130.18482080.145840894297100
4.6113-50.08330.20932410.163743304571100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
17.43056.86841.77146.24111.58310.35280.5533-0.0916-1.71540.3196-0.1828-1.02480.51280.125-0.27930.64210.0798-0.11760.553-0.05130.5614-24.075528.2568-1.9302
210.00750.68520.23675.4552-0.08235.57570.2989-0.0739-1.21430.29740.11820.17980.2016-0.5121-0.54590.4416-0.10470.1090.7526-0.0680.6034-16.499942.45642.7002
33.67971.0814-0.84541.7580.07153.25840.06320.51060.231-0.28620.1885-0.2505-0.35050.2329-0.23590.2447-0.00340.03450.3596-0.02080.3082-25.311348.18560.5528
42.1010.64680.85623.85112.02185.3560.07920.3765-0.0304-0.53710.01220.08640.0861-0.3163-0.08890.2032-0.0053-0.02170.4317-0.00450.211-44.459837.6391-6.6716
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 160 through 198 )A160 - 198
2X-RAY DIFFRACTION2chain 'A' and (resid 199 through 218 )A199 - 218
3X-RAY DIFFRACTION3chain 'A' and (resid 219 through 405 )A219 - 405
4X-RAY DIFFRACTION4chain 'A' and (resid 406 through 520 )A406 - 520

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