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

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Basic information

Entry
Database: PDB / ID: 7ftn
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with propanedioic acid
Components
  • Cyclic GMP-AMP synthase
  • DNA (5'-D(*AP*AP*AP*TP*TP*GP*CP*CP*GP*AP*AP*GP*AP*CP*GP*A)-3')
  • DNA (5'-D(*TP*CP*GP*TP*CP*TP*TP*CP*GP*GP*CP*AP*AP*TP*T)-3')
KeywordsTRANSFERASE/DNA / IMMUNE RESPONSE / TRANSFERASE / NTASE / DNA SENSOR / TRANSFERASE-DNA complex
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
FORMIC ACID / MALONATE ION / DNA / DNA (> 10) / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.001 Å
AuthorsLeibrock, L. / Benz, J. / Groebke-Zbinden, K. / Urban, R. / 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

Downloads & links

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Assembly

Deposited unit
A: Cyclic GMP-AMP synthase
B: DNA (5'-D(*AP*AP*AP*TP*TP*GP*CP*CP*GP*AP*AP*GP*AP*CP*GP*A)-3')
C: DNA (5'-D(*TP*CP*GP*TP*CP*TP*TP*CP*GP*GP*CP*AP*AP*TP*T)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,1396
Polymers51,9253
Non-polymers2133
Water4,089227
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)100.599, 100.599, 239.854
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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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: 42433.863 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

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DNA chain , 2 types, 2 molecules BC

#2: DNA chain DNA (5'-D(*AP*AP*AP*TP*TP*GP*CP*CP*GP*AP*AP*GP*AP*CP*GP*A)-3')


Mass: 4940.244 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: DNA chain DNA (5'-D(*TP*CP*GP*TP*CP*TP*TP*CP*GP*GP*CP*AP*AP*TP*T)-3')


Mass: 4550.958 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 4 types, 230 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H2O4
#6: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CH2O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / Source method: isolated from a natural source / Formula: H2O

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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: 3.37 Å3/Da / Density % sol: 63.54 %
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: 1.00003 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Nov 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2→81.89 Å / Num. obs: 49352 / % possible obs: 100 % / Redundancy: 21.618 % / Biso Wilson estimate: 44.414 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.227 / Rrim(I) all: 0.232 / Χ2: 0.778 / Net I/σ(I): 10.79 / Num. measured all: 1066892 / Scaling rejects: 38
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2-2.0519.8224.5480.3470724356935680.284.667100
2.05-2.1122.6293.2960.7278500347434690.4863.37199.9
2.11-2.1722.6522.4931.0876744338933880.5992.55100
2.17-2.2422.3982.0011.4674318331933180.7162.047100
2.24-2.3121.7741.5192.0269219318131790.8031.55599.9
2.31-2.3920.8931.2322.5265144311931180.8471.263100
2.39-2.4822.8071.0683.167647296829660.9111.09399.9
2.48-2.5822.5930.814.1865860291829150.9440.82999.9
2.58-2.722.1580.6775.0361355277027690.9570.693100
2.7-2.8321.2910.5286.3856741266526650.9680.541100
2.83-2.9821.2950.3788.8454216254825460.9830.38799.9
2.98-3.1622.4980.26512.8654446242124200.9930.271100
3.16-3.3822.0560.17918.4450397228522850.9960.183100
3.38-3.6521.2890.12824.3245409213321330.9980.131100
3.65-420.8110.1022941205198019800.9980.105100
4-4.4721.9910.08335.6239716180618060.9990.085100
4.47-5.1720.9410.07536.8833715161116100.9990.07799.9
5.17-6.3319.7470.08133.9727744140514050.9990.083100
6.33-8.9520.0120.0663922273111311130.9990.068100
8.95-58.90616.4790.0447.96115197016990.9990.04299.7

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.001→58.906 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.8 / Stereochemistry target values: ML
Details: basically a replica of 6ct9. hcGAS double mutant 161-522_K187N_L195R. the formate ion could be a partially occupied second malonate
RfactorNum. reflection% reflectionSelection details
Rfree0.2255 1910 4.9 %RANDOM
Rwork0.1848 37039 --
obs0.1868 38949 79 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 167.39 Å2 / Biso mean: 48.6814 Å2 / Biso min: 13.27 Å2
Refinement stepCycle: final / Resolution: 2.001→58.906 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2906 630 11 227 3774
Biso mean--60.23 43.37 -
Num. residues----384
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0006-2.05070.25470.27621651725
2.0507-2.10610.3748220.282140943113
2.1061-2.16810.3177570.26721209126637
2.1681-2.23810.2701890.26252020210961
2.2381-2.31810.29711430.24562803294686
2.3181-2.41090.27051660.255732893455100
2.4109-2.52060.32161800.24533073487100
2.5206-2.65350.28181680.229733243492100
2.6535-2.81980.27471570.219333393496100
2.8198-3.03750.22762020.211533063508100
3.0375-3.34310.22121790.180233613540100
3.3431-3.82680.20971790.146333723551100
3.8268-4.8210.15571580.130134803638100
4.821-58.93160.20992030.179136553858100
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)
12.4490.7711-0.11110.3728-0.0130.87760.02320.26930.1285-0.02810.07510.2106-0.0394-0.191-0.09390.18280.0176-0.01280.35850.03320.237219.7423-39.975-0.3459
25.0579-1.99960.82777.7016-0.48993.41-0.0090.6149-0.3368-0.42190.17510.3740.0478-0.5498-0.18230.2456-0.0363-0.02390.6576-0.07760.3369.9044-50.4625-7.7463
32.76820.47990.42081.4285-0.11642.63050.0560.3077-0.0278-0.05310.02350.1407-0.0709-0.1734-0.09070.10370.03170.01850.21970.02920.194427.7231-44.1235.0556
41.35510.2616-0.71782.0777-1.11582.9910.05520.29640.0505-0.2922-0.00380.0196-0.07690.0392-0.04440.12570.03420.01220.28020.03540.18140.005-36.2101-7.0639
55.80073.18850.73773.1741.13160.44110.1605-0.94890.705-0.2991-0.5790.7419-0.1108-0.18240.40220.5176-0.0801-0.09290.6755-0.02670.60638.7201-37.774416.6398
63.30751.2269-1.56648.919-0.93152.19350.2701-0.34561.8819-0.2729-0.6349-0.333-1.12030.99860.34280.7767-0.04670.04910.49190.07980.991324.7959-19.28338.6205
71.775-3.0051-1.04726.02022.37211.09520.16270.4603-0.3074-0.320.0560.3489-0.305-0.5577-0.18021.7625-0.1063-0.26590.8788-0.37911.752924.7037-6.116910.5061
84.3251-0.0912-0.58625.7316-2.2115.91830.3533-1.15861.06820.0835-0.40430.4846-0.3323-0.18490.01860.3851-0.04340.00420.7449-0.17170.599115.5512-28.763815.9564
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 161 through 253 )A161 - 253
2X-RAY DIFFRACTION2chain 'A' and (resid 254 through 307 )A254 - 307
3X-RAY DIFFRACTION3chain 'A' and (resid 308 through 405 )A308 - 405
4X-RAY DIFFRACTION4chain 'A' and (resid 406 through 520 )A406 - 520
5X-RAY DIFFRACTION5chain 'B' and (resid 1 through 10 )B1 - 10
6X-RAY DIFFRACTION6chain 'B' and (resid 11 through 15 )B11 - 15
7X-RAY DIFFRACTION7chain 'B' and (resid 16 through 16 )B16
8X-RAY DIFFRACTION8chain 'C' and (resid 2 through 16 )C2 - 16

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