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

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Basic information

Entry
Database: PDB / ID: 7ftr
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with (Z)-N-(4-acetylphenyl)-2-cyano-3-hydroxy-3-(5-methyl-1,2-oxazol-4-yl)prop-2-enamide
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
ADENOSINE-5'-TRIPHOSPHATE / : / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.64 Å
AuthorsLeibrock, L. / Benz, J. / Groebke-Zbinden, K. / Canesso, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4337
Polymers42,4051
Non-polymers1,0296
Water3,441191
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)51.061, 59.936, 125.823
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 , 6 types, 197 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-YQH / (2Z)-N-(4-acetylphenyl)-2-cyano-3-hydroxy-3-(5-methyl-1,2-oxazol-4-yl)prop-2-enamide


Mass: 311.292 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13N3O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 191 / 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: 2.27 Å3/Da / Density % sol: 45.82 %
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: Aug 23, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 1.64→62.91 Å / Num. obs: 47091 / % possible obs: 97.6 % / Redundancy: 7.147 % / Biso Wilson estimate: 30.99 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.039 / Rrim(I) all: 0.042 / Χ2: 0.861 / Net I/σ(I): 16.06 / Num. measured all: 336573 / Scaling rejects: 45
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
1.64-1.686.1414.540.317816349429010.1174.95683
1.68-1.737.0182.5320.5723175342033020.4092.73196.5
1.73-1.787.5971.7930.8724775333032610.6041.92297.9
1.78-1.837.5431.2251.2924295327932210.7821.31498.2
1.83-1.897.30.9781.6322294310630540.8451.05198.3
1.89-1.966.9110.6982.2720914306530260.8910.75598.7
1.96-2.037.5230.4044.0321876294529080.9620.43498.7
2.03-2.127.5730.2666.0621150282627930.9850.28598.8
2.12-2.217.4480.1868.620139272827040.9920.19999.1
2.21-2.327.0690.13911.2518408262726040.9950.14999.1
2.32-2.447.1720.09715.9717572246324500.9970.10599.5
2.44-2.597.5530.07321.4717674235223400.9980.07899.5
2.59-2.777.4130.05528.5616368221722080.9990.05999.6
2.77-2.996.9330.04534.6614566210521010.9990.04999.8
2.99-3.286.9910.03543.213262191018970.9990.03899.3
3.28-3.677.1760.0352.0112629176117600.9990.03299.9
3.67-4.236.6790.02754.610399156515570.9990.02999.5
4.23-5.196.4850.02556.428508132813120.9990.02798.8
5.19-7.336.6290.02656.917047106510630.9990.02899.8
7.33-29.155.8920.0255.8537066406290.9990.02298.3

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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: 1.64→29.15 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.932 / SU R Cruickshank DPI: 0.156 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.16 / SU Rfree Blow DPI: 0.144 / SU Rfree Cruickshank DPI: 0.143
Details: ligand occupies position of guanosine nucleotide. ATP binding mode and protein conformation are very similar to mouse cGAS structure 4k97 that has ATP and DNA bound. ligand density very clear.
RfactorNum. reflection% reflectionSelection details
Rfree0.252 1700 5 %RANDOM
Rwork0.217 ---
obs0.219 34003 70.8 %-
Solvent computationSolvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 179.12 Å2 / Biso mean: 50.02 Å2 / Biso min: 18.32 Å2
Baniso -1Baniso -2Baniso -3
1-3.1609 Å20 Å20 Å2
2---0.3141 Å20 Å2
3----2.8468 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: final / Resolution: 1.64→29.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2964 0 62 194 3220
Biso mean--32.05 40.76 -
Num. residues----360
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1162SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes527HARMONIC5
X-RAY DIFFRACTIONt_it3100HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion385SEMIHARMONIC5
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_contact3708SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3100HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4168HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion3.23
X-RAY DIFFRACTIONt_other_torsion18.86
LS refinement shellResolution: 1.64→1.72 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.4865 35 5.14 %
Rwork0.4523 646 -
all0.4541 681 -
obs--11.16 %
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)
12.3395-0.3566-0.29932.04560.02193.7777-0.2225-0.0254-0.5319-0.18580.0431-0.16550.76950.60970.17940.00290.18490.104-0.14780.0413-0.144920.692210.27588.7289
23.84131.1812-0.42666.3706-0.40320.0458-0.006-0.4195-0.96230.0533-0.10530.1510.6713-0.28660.11130.254-0.13830.1043-0.27050.2432-0.08130.3155-4.962223.1435
33.18920.16790.17152.514-0.5773.7455-0.1442-0.3729-0.8081-0.0742-0.0833-0.34241.19570.49370.22750.15520.19720.0786-0.29510.135-0.214315.96184.075516.8349
42.32530.70750.85831.16960.61313.5747-0.1348-0.37660.0255-0.0434-0.01970.04710.25690.07980.1545-0.07020.0803-0.0154-0.05630.0087-0.135611.5323.160120.049
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|162 - A|233 }A162 - 233
2X-RAY DIFFRACTION2{ A|234 - A|272 }A234 - 272
3X-RAY DIFFRACTION3{ A|273 - A|345 }A273 - 345
4X-RAY DIFFRACTION4{ A|346 - A|521 }A346 - 521

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