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

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Basic information

Entry
Database: PDB / ID: 7fun
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with 2-[(4-benzylpiperazin-1-yl)methyl]-6-(2-chloro-4-methylphenyl)-1H-benzimidazole-4-carboxylic 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 / cGMP-mediated signaling ...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 / cGMP-mediated signaling / 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 / cAMP-mediated signaling / 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 / nucleus / metal ion binding / 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
IODIDE ION / : / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsLeibrock, L. / Benz, J. / Groebke-Zbinden, K. / Galley, G. / 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)43,90512
Polymers42,4051
Non-polymers1,50011
Water1,04558
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)44.574, 59.125, 163.046
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221

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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: 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

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Non-polymers , 5 types, 69 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-YU6 / (5M)-2-[(4-benzylpiperazin-1-yl)methyl]-5-(2-chloro-4-methylphenyl)-1H-benzimidazole-7-carboxylic acid


Mass: 474.982 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H27ClN4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: I
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 58 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.53 Å3/Da / Density % sol: 51.45 %
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: 1.00005 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 22, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00005 Å / Relative weight: 1
ReflectionResolution: 2.07→59.12 Å / Num. obs: 27202 / % possible obs: 99.9 % / Redundancy: 6.435 % / Biso Wilson estimate: 60.83 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.04 / Rrim(I) all: 0.043 / Χ2: 0.875 / Net I/σ(I): 16.9 / Num. measured all: 175042 / Scaling rejects: 7
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
2.07-2.126.6912.9530.6213550202520250.2143.202100
2.12-2.186.6621.9830.9312725191019100.3512.151100
2.18-2.256.2771.391.3111706186518650.5871.517100
2.25-2.316.560.8842.0711899181618140.7230.96199.9
2.31-2.396.8640.6472.912054175617560.8540.7100
2.39-2.476.7950.4464.1211816174017390.9330.48399.9
2.47-2.576.6640.2836.2810843162716270.9720.307100
2.57-2.676.4870.1998.7110372159915990.9830.216100
2.67-2.796.1450.14711.159469154115410.9890.161100
2.79-2.936.8250.1116.359964146014600.9940.119100
2.93-3.096.720.07422.649428140314030.9970.08100
3.09-3.276.5570.05728.268681132513240.9980.06299.9
3.27-3.56.1960.042357826126512630.9990.04699.8
3.5-3.786.1230.03639.627091116211580.9990.03999.7
3.78-4.146.4170.03345.217014109610930.9990.03699.7
4.14-4.636.150.0346.5660829909890.9990.03399.9
4.63-5.345.490.0344.2348598858850.9990.032100
5.34-6.555.8240.03245.3244677687670.9990.03499.9
6.55-9.265.4610.02845.64332060960810.03199.8
9.26-30.084.9890.02444.5218763803760.9990.02798.9

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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: 2.07→30.08 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.874 / SU R Cruickshank DPI: 0.27 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.27 / SU Rfree Blow DPI: 0.228 / SU Rfree Cruickshank DPI: 0.23
Details: crystallized with 0.2M KI, large negative Fo-Fc peaks indicate low occupancy prescence of iodide determined by anomalous difference density >5rmsd. ligand well defined by electron density.
RfactorNum. reflection% reflectionSelection details
Rfree0.294 1138 4.97 %RANDOM
Rwork0.24 ---
obs0.243 22894 84.5 %-
Solvent computationSolvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 225.21 Å2 / Biso mean: 93.27 Å2 / Biso min: 42.09 Å2
Baniso -1Baniso -2Baniso -3
1--0.9779 Å20 Å20 Å2
2---1.0812 Å20 Å2
3---2.059 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.07→30.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2849 0 44 58 2951
Biso mean--67.9 66.8 -
Num. residues----346
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1091SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes483HARMONIC5
X-RAY DIFFRACTIONt_it2942HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion366SEMIHARMONIC5
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_contact3256SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2942HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3943HARMONIC21.1
X-RAY DIFFRACTIONt_omega_torsion2.73
X-RAY DIFFRACTIONt_other_torsion19.55
LS refinement shellResolution: 2.07→2.18 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.5558 21 4.59 %
Rwork0.448 437 -
all0.4524 458 -
obs--12.46 %
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)
17.19242.7212-0.51629.04511.25323.8212-0.06871.2587-1.397-0.43130.14570.3459-0.2476-1.0955-0.0771-0.36570.15180.05220.144-0.0565-0.0664-10.7397-18.2255-25.6107
29.13941.46221.1832.23361.58484.8769-0.11160.4981-1.63270.17510.0502-0.05920.49590.42070.0614-0.36770.08780.1537-0.2696-0.17720.3669.1028-31.342-20.8467
36.33642.11452.36794.91782.30627.9466-0.24771.3816-1.6327-0.39760.19590.27030.55830.05770.0518-0.4318-0.02040.1656-0.0175-0.44560.30422.2014-31.1046-29.4596
45.8841-0.5904-1.94711.95250.2375.05360.39730.72730.3648-0.20960.009-0.1169-1.19640.1519-0.4063-0.0009-0.03830.1572-0.19170.096-0.20316.8411-7.8541-21.2618
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|161 - A|198 }A161 - 198
2X-RAY DIFFRACTION2{ A|199 - A|272 }A199 - 272
3X-RAY DIFFRACTION3{ A|273 - A|334 }A273 - 334
4X-RAY DIFFRACTION4{ A|335 - A|521 }A335 - 521

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