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

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Basic information

Entry
Database: PDB / ID: 7ftm
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with 2-[2-(4-fluoroanilino)-1,3-thiazol-4-yl]acetic acid
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: 1.698 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

Downloads & links

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Assembly

Deposited unit
A: Cyclic GMP-AMP synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9754
Polymers42,4051
Non-polymers5703
Water2,450136
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, elutes as a monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.268, 59.837, 125.041
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-YO6 / [2-(4-fluoroanilino)-1,3-thiazol-4-yl]acetic acid


Mass: 252.265 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H9FN2O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 136 / 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: 2.13 Å3/Da / Density % sol: 42.23 %
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: 1.00001 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 1.7→59.84 Å / Num. obs: 40847 / % possible obs: 99.9 % / Redundancy: 7.259 % / Biso Wilson estimate: 44.396 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rrim(I) all: 0.063 / Χ2: 0.856 / Net I/σ(I): 14.88 / Num. measured all: 296495 / Scaling rejects: 10
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
1.7-1.747.4623.4090.5222140297029670.1993.66699.9
1.74-1.797.4012.3230.821633292429230.2892.501100
1.79-1.847.1081.6231.2119817279127880.481.75499.9
1.84-1.97.1431.2861.5619558274027380.6191.38899.9
1.9-1.967.5870.8952.4220249266926690.7740.962100
1.96-2.037.4930.5743.7519348258325820.9010.617100
2.03-2.117.3880.3835.4618388249324890.9570.41299.8
2.11-2.197.1730.2727.4417359242124200.9780.294100
2.19-2.297.0390.2159.4916050228022800.980.232100
2.29-2.47.5990.14613.8816999223722370.9920.157100
2.4-2.537.5480.11516.9315829209820970.9950.124100
2.53-2.687.3890.08820.9714807200520040.9960.095100
2.68-2.876.9080.06924.713008188318830.9970.075100
2.87-3.17.3040.05132.0112811175417540.9980.055100
3.1-3.47.4270.04238.6712143163916350.9990.04599.8
3.4-3.87.1590.03543.2810609148414820.9990.03899.9
3.8-4.386.5260.03146.238628132613220.9990.03499.7
4.38-5.377.1230.02950.678149114611440.9990.03299.8
5.37-7.596.4670.03347.6357438958880.9990.03599.2
7.59-59.8375.9210.03149.3532275525450.9990.03498.7

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIXdev_3139refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 1.698→59.837 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.25 / Stereochemistry target values: ML
Details: ligand not well defined by electron density, was built in two alternate conformations. a second ligand molecule is likely bound near the N-terminus.
RfactorNum. reflection% reflectionSelection details
Rfree0.2321 1660 5 %RANDOM
Rwork0.1901 31550 --
obs0.1922 33210 81.25 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 183.19 Å2 / Biso mean: 60.9431 Å2 / Biso min: 19.02 Å2
Refinement stepCycle: final / Resolution: 1.698→59.837 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2934 0 52 136 3122
Biso mean--73.28 43.27 -
Num. residues----356
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6976-1.74750.279260.32491841906
1.7475-1.80390.3093440.325677181524
1.8039-1.86840.3656930.29281678177153
1.8684-1.94320.3111800.26932833301390
1.9432-2.03170.2531690.226431873356100
2.0317-2.13880.22241630.210932113374100
2.1388-2.27280.24221650.195132183383100
2.2728-2.44830.24461760.197932153391100
2.4483-2.69460.22091660.203632323398100
2.6946-3.08460.22471580.210332803438100
3.0846-3.88610.21591800.180832673447100
3.8861-59.87420.23141600.164134743634100
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)
13.016-2.83160.76442.7674-0.63651.5397-0.3001-0.31470.83241.16850.1181-1.1667-0.28660.15320.21480.44430.0571-0.07070.5359-0.08540.511425.4527-14.6458-7.1331
22.44241.66790.49973.0073-0.0145.2221-0.14060.09181.0720.1089-0.01170.1096-0.6803-0.12930.11730.62670.1008-0.09430.31830.01970.77327.93610.3337-16.1296
32.4224-0.43920.27062.6141-0.91762.6644-0.03640.25390.7103-0.0438-0.1777-0.442-0.59880.31710.03740.3145-0.0469-0.01060.2460.07750.412911.6926-8.6825-14.0119
43.0935-0.7935-0.45912.4075-0.46613.35530.00310.41840.0018-0.4345-0.0455-0.14340.20.30140.03830.2346-0.02010.00060.2382-0.04350.168814.8681-27.4458-22.7481
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 405 )A273 - 405
4X-RAY DIFFRACTION4chain 'A' and (resid 406 through 521 )A406 - 521

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