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- PDB-7fu2: Crystal Structure of human cyclic GMP-AMP synthase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 7fu2
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with 6-(2-chloro-5-fluoro-4-methylphenyl)-1H-benzimidazole-4-carboxylic acid
ComponentsCyclic GMP-AMP synthase
KeywordsTRANSFERASE / IMMUNE RESPONSE / NTASE / DNA SENSOR
Function / homology
Function and homology information


cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / cGAS/STING signaling pathway / regulation of immunoglobulin production / regulation of T cell activation / pattern recognition receptor signaling pathway / negative regulation of double-strand break repair via homologous recombination ...cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / cGAS/STING signaling pathway / regulation of immunoglobulin production / regulation of T cell activation / pattern recognition receptor signaling pathway / negative regulation of double-strand break repair via homologous recombination / negative regulation of cGAS/STING signaling pathway / cellular response to exogenous dsRNA / cytoplasmic pattern recognition receptor signaling pathway / cGMP-mediated signaling / cAMP-mediated signaling / nucleosome binding / positive regulation of type I interferon production / positive regulation of defense response to virus by host / phosphatidylinositol-4,5-bisphosphate binding / activation of innate immune response / molecular condensate scaffold activity / determination of adult lifespan / positive regulation of cellular senescence / site of double-strand break / double-stranded DNA binding / defense response to virus / nuclear body / DNA repair / innate immune response / 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-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21
Similarity search - Domain/homology
: / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsLeibrock, L. / Benz, J. / Groebke-Zbinden, K. / Zhou, C. / 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)42,7753
Polymers42,4051
Non-polymers3702
Water57632
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)43.142, 58.503, 161.989
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-YM9 / (5M)-5-(2-chloro-5-fluoro-4-methylphenyl)-1H-benzimidazole-7-carboxylic acid


Mass: 304.704 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H10ClFN2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 2.41 Å3/Da / Density % sol: 48.97 %
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: Feb 8, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2.3→58.5 Å / Num. obs: 18816 / % possible obs: 98.8 % / Redundancy: 6.823 % / Biso Wilson estimate: 66.31 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.048 / Rrim(I) all: 0.053 / Χ2: 0.861 / Net I/σ(I): 15.22 / Num. measured all: 128382 / Scaling rejects: 16
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
2.3-2.364.6283.8730.245720138412360.1214.36189.3
2.36-2.425.4053.8370.337161135713250.1284.23697.6
2.42-2.496.7522.4890.668616128612760.4482.69699.2
2.49-2.577.5551.7371.139572126812670.6861.86599.9
2.57-2.667.4331.2731.579165123912330.7591.36999.5
2.66-2.757.380.952.138679118011760.8471.02299.7
2.75-2.857.0340.6652.868096115311510.8970.71999.8
2.85-2.977.180.3984.688049112411210.9820.42999.7
2.97-3.17.5070.296.58077108010760.9810.31299.6
3.1-3.257.3150.1999.417447101910180.9870.21499.9
3.25-3.437.1410.11914.6269629789750.9950.12999.7
3.43-3.646.8180.08220.6864989539530.9980.089100
3.64-3.897.3420.05829.3263518668650.9990.06399.9
3.89-4.27.190.04835.3659108228220.9990.051100
4.2-4.66.7320.03442.6651037597580.9990.03799.9
4.6-5.147.030.03147.9148516896900.9990.034100
5.14-5.947.0720.03249.6644916366350.9990.03499.8
5.94-7.276.3030.0349.7734485475470.9990.032100
7.27-10.296.5440.02259.74276842642310.02499.3
10.29-47.425.2710.01859.83141827026910.0299.6

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.3→47.42 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.659 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.673 / SU Rfree Blow DPI: 0.324 / SU Rfree Cruickshank DPI: 0.327
RfactorNum. reflection% reflectionSelection details
Rfree0.287 698 4.93 %RANDOM
Rwork0.249 ---
obs0.251 14169 74.9 %-
Solvent computationSolvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 196.16 Å2 / Biso mean: 93.89 Å2 / Biso min: 28.96 Å2
Baniso -1Baniso -2Baniso -3
1-6.2432 Å20 Å20 Å2
2--0.6397 Å20 Å2
3----6.8829 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: final / Resolution: 2.3→47.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2831 0 22 32 2885
Biso mean--46.86 55.52 -
Num. residues----343
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1073SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes480HARMONIC5
X-RAY DIFFRACTIONt_it2907HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion365SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3217SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2907HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3900HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.24
X-RAY DIFFRACTIONt_other_torsion21.22
LS refinement shellResolution: 2.3→2.4 Å / Rfactor Rfree error: 0 / Total num. of bins used: 34
RfactorNum. reflection% reflection
Rfree0.7773 21 5.04 %
Rwork0.595 396 -
all0.6033 417 -
obs--18.65 %
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)
14.1956-0.92-2.14377.19532.67937.4167-0.05410.941-1.4742-0.357-0.18810.45920.7043-0.25370.2422-0.3482-0.05880.1355-0.2696-0.2498-0.14113.2808-28.181-23.856
25.8777-0.8308-2.0462.20450.50717.61510.21160.62630.3454-0.27750.1361-0.307-0.92880.2584-0.3476-0.1442-0.14830.0663-0.19130.0243-0.32277.9302-8.7887-20.3209
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|161 - A|315 }A161 - 315
2X-RAY DIFFRACTION2{ A|316 - A|521 }A316 - 521

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