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- PDB-7fu1: Crystal Structure of human cyclic GMP-AMP synthase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 7fu1
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with 5-[3-[[(5-bromo-2-hydroxybenzoyl)amino]methyl]phenyl]-2-methylpyrazole-3-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 / : ...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 / 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: 2.074 Å
AuthorsLeibrock, L. / Benz, J. / Groebke-Zbinden, K. / 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)42,9013
Polymers42,4051
Non-polymers4962
Water99155
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)45.355, 59.530, 162.596
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-YU2 / (3P)-3-{3-[(5-bromo-2-hydroxybenzamido)methyl]phenyl}-1-methyl-1H-pyrazole-5-carboxylic acid


Mass: 430.252 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16BrN3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 55 / 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: 2.59 Å3/Da / Density % sol: 52.48 %
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: 2.07→59.53 Å / Num. obs: 27059 / % possible obs: 98 % / Redundancy: 6.505 % / Biso Wilson estimate: 70.382 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.077 / Rrim(I) all: 0.084 / Χ2: 0.86 / Net I/σ(I): 9.61 / Num. measured all: 176032 / Scaling rejects: 739
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
2.07-2.137.2596.7430.4514300201719700.2527.26297.7
2.13-2.197.0712.4050.9513563193019180.4352.59599.4
2.19-2.256.3217.0360.8111170190117670.7287.71193
2.25-2.327.0232.5851.3912010185017100.7172.80392.4
2.32-2.397.4220.8912.9713129179517690.8820.95798.6
2.39-2.487.2760.6833.7512559174217260.9250.73599.1
2.48-2.576.9790.4644.9811529166516520.9580.50199.2
2.57-2.686.5610.366.2910583163016130.9630.39299
2.68-2.86.2390.2717.759577155215350.9750.29698.9
2.8-2.935.7780.1829.828425148314580.9820.20198.3
2.93-3.096.1730.12213.598691142514080.9920.13398.8
3.09-3.286.1230.09816.478297136513550.9930.10799.3
3.28-3.515.8030.08418.57306127612590.9940.09298.7
3.51-3.795.6490.08119.636649118811770.9940.08999.1
3.79-4.155.2110.0720.195701110810940.9950.07798.7
4.15-4.646.0760.06323.37596710029820.9960.06898
4.64-5.366.4820.05924.5457888948930.9950.06499.9
5.36-6.566.3050.05523.8848937777760.9960.0699.9
6.56-9.285.8170.04623.5635896236170.9990.0599
9.28-59.536.0680.03724.6123063833800.9970.04199.2

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.074→59.53 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 38.53 / Stereochemistry target values: ML
Details: orientation of methylpyrazole based on electron density. Other rotamer also possible.
RfactorNum. reflection% reflectionSelection details
Rfree0.2757 1117 5.15 %RANDOM
Rwork0.2225 20553 --
obs0.2253 21670 78.66 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 200.87 Å2 / Biso mean: 72.7849 Å2 / Biso min: 28.05 Å2
Refinement stepCycle: final / Resolution: 2.074→59.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2888 0 28 55 2971
Biso mean--57.24 54.91 -
Num. residues----351
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0742-2.16860.2992130.330431332610
2.1686-2.28290.6503750.43291262133740
2.2829-2.42590.31561500.30692667281783
2.4259-2.61320.39961820.30753154333698
2.6132-2.87620.31991690.2973222339199
2.8762-3.29240.34031560.25883250340699
3.2924-4.14790.28771680.20553276344499
4.1479-59.55450.21072040.17343409361399
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)
12.1144-0.8256-0.58651.7422-0.35131.583-0.306-0.2898-0.7168-0.10.1366-0.09850.0770.12740.14950.4145-0.00920.07120.44420.03270.515622.66535.608321.9237
28.45711.60890.4395.1034-1.13484.17080.1938-1.1476-1.56310.5267-0.10310.06020.9049-0.085-0.06450.59690.04450.14380.50810.26580.834518.1072-5.299927.5819
33.43220.0893-0.44522.37190.43514.2920.112-0.26710.27020.1923-0.01450.2291-0.55-0.3232-0.0770.29410.06840.01860.2804-0.02970.260515.132221.97820.2397
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 161 through 253 )A161 - 253
2X-RAY DIFFRACTION2chain 'A' and (resid 254 through 326 )A254 - 326
3X-RAY DIFFRACTION3chain 'A' and (resid 327 through 520 )A327 - 520

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