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

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Basic information

Entry
Database: PDB / ID: 7fub
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with 6-(2-chloro-4-methylphenyl)-3-(pyridin-4-ylmethyl)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 / : ...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 / cytoplasm / cytosol
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
ADENOSINE-5'-TRIPHOSPHATE / : / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.981 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)43,3805
Polymers42,4051
Non-polymers9754
Water1,60389
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)47.588, 60.279, 126.529
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221
Components on special symmetry positions
IDModelComponents
11A-604-

MG

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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, 93 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-YQ3 / (5M)-5-(2-chloro-4-methylphenyl)-1-[(pyridin-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid


Mass: 377.824 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16ClN3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


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


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 89 / 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: 2.14 Å3/Da / Density % sol: 42.52 %
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 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.98→63.26 Å / Num. obs: 26109 / % possible obs: 99.9 % / Redundancy: 6.52 % / Biso Wilson estimate: 48.85 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.23 / Rrim(I) all: 0.25 / Χ2: 0.72 / Net I/σ(I): 6.54 / Num. measured all: 170223 / Scaling rejects: 22
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible allCC1/2
1.98-2.036.8178.280.2612897189618928.95999.8
2.03-2.096.6975.6250.3812383185018496.09599.9
2.09-2.156.6214.7890.4711978181018095.19699.90.193
2.15-2.216.3183.4190.6410949173417333.72599.90.251
2.21-2.296.4832.7040.8110949169016892.94199.90.371
2.29-2.376.7851.8531.2711135164216412.00699.90.514
2.37-2.466.7651.5311.5210777159315931.6581000.558
2.46-2.566.5961.1581.9110198154715461.25799.90.657
2.56-2.676.3170.9012.59178145414530.98299.90.786
2.67-2.86.3090.6363.398977142414230.69399.90.87
2.8-2.956.7860.4534.899100134213410.4999.90.942
2.95-3.136.6730.3146.728508127512750.3411000.969
3.13-3.356.510.2059.487929121812180.2231000.984
3.35-3.626.0830.12314.166849112711260.13599.90.992
3.62-3.966.7260.09318.917029104510450.1011000.995
3.96-4.436.5930.07122.6962179439430.0771000.997
4.43-5.126.040.06323.9952258658650.0691000.997
5.12-6.266.2480.06623.0545057227210.07299.90.997
6.26-8.866.0840.05226.7535415825820.0571000.998
8.86-63.2645.2030.02736.8318993673650.0399.50.999

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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: 1.981→63.264 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 33.06 / Stereochemistry target values: ML / Details: ligand well defined by electron density
RfactorNum. reflection% reflectionSelection details
Rfree0.273 787 5.08 %RANDOM
Rwork0.1882 14710 --
obs0.1925 15497 59.4 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 145.92 Å2 / Biso mean: 50.5886 Å2 / Biso min: 10.29 Å2
Refinement stepCycle: final / Resolution: 1.981→63.264 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2968 0 42 89 3099
Biso mean--54.09 35.4 -
Num. residues----361
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.9808-2.10490.211750.32531251303
2.1049-2.26740.4157330.290574778018
2.2674-2.49560.3192990.26821913201247
2.4956-2.85670.33951960.26023449364585
2.8567-3.59910.29392250.201641444369100
3.5991-63.29680.22892290.143743324561100
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)
12.1802-0.42480.42863.9689-0.04011.2989-0.14710.01470.65010.24430.1138-0.2811-0.56080.15410.04590.3553-0.0380.06760.33180.0430.376216.145-8.715-12.9391
22.630.17280.07971.8887-0.22171.4808-0.11580.51440.806-0.2197-0.0087-0.1987-0.69940.0519-0.02680.4156-0.0346-0.01310.23440.13980.415710.3328-7.0734-15.925
32.9408-0.3226-0.43222.0463-0.33152.985-0.01190.4396-0.1153-0.385-0.11470.02880.0330.19660.11250.1322-0.0213-0.02160.2124-0.03750.158514.6592-28.0849-22.9234
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 405 )A254 - 405
3X-RAY DIFFRACTION3chain 'A' and (resid 406 through 521 )A406 - 521

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