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

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Basic information

Entry
Database: PDB / ID: 7fuo
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one
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 / 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
: / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.81 Å
AuthorsLeibrock, L. / Benz, J. / Groebke-Zbinden, K. / Brunner, M. / 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)42,8693
Polymers42,4051
Non-polymers4642
Water84747
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)46.852, 58.781, 163.918
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221

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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: 42404.906 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-YUB / (8R)-2-{[(2-chlorophenyl)methyl]amino}-5-[(2-fluoroanilino)methyl][1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one


Mass: 398.821 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16ClFN6O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / 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: 2.66 Å3/Da / Density % sol: 53.78 %
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: 0.99999 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jul 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 1.81→55.33 Å / Num. obs: 40899 / % possible obs: 96.7 % / Redundancy: 6.409 % / Biso Wilson estimate: 63.647 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.042 / Rrim(I) all: 0.046 / Χ2: 0.813 / Net I/σ(I): 14.54 / Num. measured all: 262115 / Scaling rejects: 65
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
1.81-1.865.0557.0620.1311046305821857.86571.5
1.86-1.915.6378.1530.1215592301427668.97191.8
1.91-1.966.6757.4150.1919184293228748.043980.167
1.96-2.026.8324.1620.4119136284428014.50798.50.392
2.02-2.096.7362.9980.618187273827003.2598.60.546
2.09-2.166.5831.9060.9217319265326312.0799.20.723
2.16-2.256.3041.0381.6216246259125771.13299.50.883
2.25-2.346.8730.7622.3416963248524680.82599.30.936
2.34-2.446.810.5433.2916132239023690.58999.10.956
2.44-2.566.6470.3255.1715088228722700.35399.30.985
2.56-2.76.30.1937.8413653218121670.2199.40.993
2.7-2.866.7230.13411.5813802206020530.14699.70.997
2.86-3.066.7530.08718.0113229196219590.09599.80.998
3.06-3.36.6110.05827.0411960181618090.06399.60.999
3.3-3.626.1540.03839.8510449170416980.04199.60.999
3.62-4.056.6320.02756.8510048151815150.02999.81
4.05-4.676.3510.021678815139313880.02399.61
4.67-5.725.8160.0268.776811117511710.02299.71
5.72-8.095.9410.01969.0455139309280.02199.81
8.09-55.3315.1610.01574.5829425795700.01698.41

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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: 1.81→55.331 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 39.65 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2592 1171 5.15 %RANDOM
Rwork0.1968 21546 --
obs0.1999 22717 53.79 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 143.38 Å2 / Biso mean: 61.8423 Å2 / Biso min: 25.21 Å2
Refinement stepCycle: final / Resolution: 1.81→55.331 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2876 0 29 47 2952
Biso mean--42.51 50.54 -
Num. residues----350
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8103-1.89270.4301120.34581351473
1.8927-1.99250.4962340.359451454811
1.9925-2.11730.3645540.3329963101719
2.1173-2.28080.31551060.30411681178734
2.2808-2.51030.34181480.30053036318461
2.5103-2.87360.34012750.26944894516998
2.8736-3.62030.30882730.215150495322100
3.6203-55.35680.19692690.149552745543100
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)
11.430.71670.62556.6772-0.08980.85990.0565-0.2297-0.23180.3398-0.3558-1.4703-0.12180.39010.25480.4573-0.00880.03290.56950.1070.393935.329612.384125.3241
23.4497-1.1918-0.46053.7045-0.43782.60210.06940.1145-0.55210.2062-0.02480.59880.3739-0.27930.01170.4344-0.04720.04470.3940.01610.437815.9465-2.51722.5047
31.84-0.7348-0.25393.9078-1.37453.0985-0.1532-0.2096-0.36410.56390.00470.09170.0488-0.03890.04670.3782-0.0410.0460.39050.01910.275419.81823.906623.1594
42.68280.0489-0.55663.2452-0.07563.67420.1844-0.29430.15050.7979-0.08370.1551-0.51950.0346-0.02150.5318-0.03430.04460.3022-0.01140.106817.754726.229223.6279
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 161 through 199 )A161 - 199
2X-RAY DIFFRACTION2chain 'A' and (resid 200 through 272 )A200 - 272
3X-RAY DIFFRACTION3chain 'A' and (resid 273 through 389 )A273 - 389
4X-RAY DIFFRACTION4chain 'A' and (resid 390 through 521 )A390 - 521

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