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- PDB-7fu9: Crystal Structure of human cyclic GMP-AMP synthase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 7fu9
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with 2-[(2-chloro-5-pyridin-4-ylphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one
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
: / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.668 Å
AuthorsLeibrock, L. / Benz, J. / Groebke-Zbinden, K. / Hunziker, D. / 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)42,8653
Polymers42,4051
Non-polymers4602
Water2,900161
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)47.656, 58.578, 126.008
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-YOB / (8S)-2-({[2-chloro-5-(pyridin-4-yl)phenyl]methyl}amino)-5-propyl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one


Mass: 394.857 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19ClN6O / 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.: 161 / 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: 2.07 Å3/Da / Density % sol: 40.69 %
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: 0.99989 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 29, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99989 Å / Relative weight: 1
ReflectionResolution: 1.67→58.58 Å / Num. obs: 41967 / % possible obs: 99.9 % / Redundancy: 6.446 % / Biso Wilson estimate: 44.033 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.094 / Rrim(I) all: 0.102 / Χ2: 0.784 / Net I/σ(I): 7.95 / Num. measured all: 270527 / Scaling rejects: 77
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
1.67-1.716.0965.6510.2918568305130460.1956.17999.8
1.71-1.766.473.2770.5419366299729930.3213.56399.9
1.76-1.816.752.4620.7619379287228710.4462.666100
1.81-1.866.6921.7691.118805281328100.5891.91799.9
1.86-1.936.5941.3171.4718108274927460.7161.42999.9
1.93-1.996.4260.8992.1517029265526500.8380.97899.8
1.99-2.076.0610.6212.9315607257625750.890.68100
2.07-2.156.7270.4484.1716555246224610.9430.485100
2.15-2.256.7240.3145.7315902236723650.9780.3499.9
2.25-2.366.680.2337.4715196227522750.9830.252100
2.36-2.496.5690.1938.8514241216921680.9870.21100
2.49-2.646.10.13510.9612511205120510.9930.148100
2.64-2.826.590.1113.6612798194419420.9950.11999.9
2.82-3.056.7010.08517.0211961178817850.9970.09299.8
3.05-3.346.4640.07120.0810860168216800.9970.07799.9
3.34-3.735.9030.06222.219050153415330.9960.06899.9
3.73-4.316.1820.05924.218407136013600.9970.064100
4.31-5.276.480.06126.527607117711740.9960.06699.7
5.27-7.465.7770.06524.9953389259240.9930.07299.9
7.46-53.1195.8050.06225.9332395625580.9970.06799.3

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.15rc1_3423refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 1.668→53.119 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 33.26 / Stereochemistry target values: ML / Details: ligand well defined by electron density
RfactorNum. reflection% reflectionSelection details
Rfree0.2584 1518 5.03 %RANDOM
Rwork0.1949 28650 --
obs0.198 30168 72 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 151.31 Å2 / Biso mean: 51.1398 Å2 / Biso min: 12.87 Å2
Refinement stepCycle: final / Resolution: 1.668→53.119 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2865 0 29 161 3055
Biso mean--38.78 39.92 -
Num. residues----348
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6685-1.72240.4308110.33571651765
1.7224-1.78390.2795330.310264868118
1.7839-1.85530.3612620.28361215127734
1.8553-1.93980.32761220.27111950207255
1.9398-2.04210.31991400.24042779291977
2.0421-2.170.30541890.24013535372498
2.17-2.33760.26151900.211635753765100
2.3376-2.57280.29111890.206536083797100
2.5728-2.94510.27851990.214436463845100
2.9451-3.71030.22642150.189336453860100
3.7103-53.14570.23871680.163638844052100
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)
12.0949-2.44020.17517.247-0.02191.7512-0.3111-0.11060.55620.75510.2393-1.056-0.59820.05110.06220.41170.0916-0.09520.3209-0.0140.364725.5515-13.5262-7.681
25.02140.25290.85834.9453-0.00642.8284-0.2711-0.03640.3439-0.43710.25270.1017-0.6901-0.04460.02260.80220.0155-0.06330.28060.0420.385911.57242.2747-17.0298
37.2084-2.8463-0.04788.29870.49021.9919-0.62430.5741.1657-0.74290.7041-0.7901-0.36290.1339-0.1340.6148-0.19870.13580.58550.02890.856729.0077-1.473-18.1353
42.57620.33970.47623.4388-0.66251.9252-0.07040.24390.3252-0.15610.04180.2195-0.5182-0.0749-0.02050.2820.0449-0.02720.18350.02640.21334.1308-9.6344-14.3268
51.8079-0.1867-0.36541.1767-0.15612.3415-0.00210.311-0.0521-0.3079-0.0702-0.07430.09120.26610.06610.15220.01010.00520.2079-0.00980.150813.9232-26.5821-20.0664
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 290 )A200 - 290
3X-RAY DIFFRACTION3chain 'A' and (resid 291 through 315 )A291 - 315
4X-RAY DIFFRACTION4chain 'A' and (resid 316 through 388 )A316 - 388
5X-RAY DIFFRACTION5chain 'A' and (resid 389 through 521 )A389 - 521

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