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- PDB-7fu5: Crystal Structure of human cyclic GMP-AMP synthase -

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Basic information

Entry
Database: PDB / ID: 7fu5
TitleCrystal Structure of human cyclic GMP-AMP synthase
ComponentsCyclic GMP-AMP synthase
KeywordsTRANSFERASE / NUCLEOTIDYLTRANSFERASE / CYCLIC GMP-AMP SYNTHASE / CGAS / DNA-BINDING / ACTIVATOR DNA / PATTERN RECOGNITION RECEPTOR / INNATE IMMUNE RESPONSE / VIRAL DNA RECOGNITION
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
: / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.18 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

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Assembly

Deposited unit
A: Cyclic GMP-AMP synthase
B: Cyclic GMP-AMP synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,9849
Polymers84,8102
Non-polymers1,1747
Water1,856103
1
A: Cyclic GMP-AMP synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8483
Polymers42,4051
Non-polymers4432
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cyclic GMP-AMP synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,1366
Polymers42,4051
Non-polymers7315
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)219.993, 45.554, 89.978
Angle α, β, γ (deg.)90.000, 111.380, 90.000
Int Tables number5
Space group name H-MC121

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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.: 2 / 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.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-YMO / (8S)-2-{[(3-fluoro[1,1'-biphenyl]-4-yl)methyl]amino}-5-propyl[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one


Mass: 377.415 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H20FN5O
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / Source method: isolated from a natural source / Formula: H2O

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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: 2.48 Å3/Da / Density % sol: 50.31 %
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 23, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2.18→80.89 Å / Num. obs: 43609 / % possible obs: 99.5 % / Redundancy: 3.354 % / Biso Wilson estimate: 40.7 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.096 / Rrim(I) all: 0.114 / Χ2: 0.797 / Net I/σ(I): 7.52 / Num. measured all: 146267 / Scaling rejects: 46
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
2.18-2.243.4023.3270.4310869320731950.1573.95299.6
2.24-2.33.3522.460.5810475314131250.2552.93299.5
2.3-2.373.1572.0830.689550303330250.2982.51199.7
2.37-2.443.4351.530.9910092294729380.4031.81899.7
2.44-2.523.4851.091.410020289128750.6161.29199.4
2.52-2.613.4670.8921.729483275127350.7081.05599.4
2.61-2.713.3890.7322.089027268526640.8010.86999.2
2.71-2.823.2750.5142.828452259925810.8180.61599.3
2.82-2.943.1950.3793.67828246224500.9020.45699.5
2.94-3.093.4680.2675.448261238923820.9450.31699.7
3.09-3.253.4750.1897.267822226622510.9720.22499.3
3.25-3.453.4370.13110.27368215221440.9830.15699.6
3.45-3.693.260.08513.396451198819790.9920.10299.5
3.69-3.993.2890.06516.886209189718880.9940.07899.5
3.99-4.373.4890.04821.426032173717290.9970.05799.5
4.37-4.883.4120.041245408159315850.9980.04899.5
4.88-5.643.0830.0422.724344142214090.9980.04899.1
5.64-6.93.3780.04223.773966118111740.9970.0599.4
6.9-9.763.2040.0312929969429350.9970.03799.3
9.76-55.672.9610.02732.5316145555450.9980.03398.2

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.18→55.67 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 37.85 / Stereochemistry target values: ML
Details: different crystal form than 4gas3, which has the same ligand;
RfactorNum. reflection% reflectionSelection details
Rfree0.2784 1425 4.91 %RANDOM
Rwork0.2206 27572 --
obs0.2235 28997 66.24 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 146.18 Å2 / Biso mean: 51.2282 Å2 / Biso min: 17.44 Å2
Refinement stepCycle: final / Resolution: 2.18→55.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5827 0 73 103 6003
Biso mean--46.57 39.19 -
Num. residues----708
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.18-2.260.3592100.32591641744
2.26-2.350.3433420.333867872017
2.35-2.460.3637650.32541508157336
2.46-2.590.32071070.3042084219150
2.59-2.750.39421310.31322887301870
2.75-2.960.35241910.3043546373785
2.96-3.260.33942220.28024070429298
3.26-3.730.27882050.206941604365100
3.73-4.70.22972180.176541744392100
4.7-55.670.24672340.18644301453599
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)
12.18880.42780.03810.73880.12050.46620.2837-0.1387-0.27640.1428-0.2926-0.02690.19530.10470.0760.3794-0.06190.00340.28940.02390.4172-44.9838-35.308317.7696
21.5731-1.1479-0.24791.4381-0.25811.19620.0093-0.14340.0939-0.03230.0456-0.299-0.01030.3376-0.00740.2052-0.1849-0.05560.42790.0190.4395-31.3678-17.376621.1117
33.8639-0.8195-0.51563.7005-0.08613.9152-0.1275-0.0822-0.1381-0.5149-0.1511-0.60870.16130.524-0.02090.2698-0.15370.0480.50240.05020.589-31.9545-28.93487.6955
41.4791-0.28720.1031.1007-0.0681.76260.0886-0.0303-0.0941-0.0329-0.0535-0.0824-0.00790.09910.01420.217-0.08670.02690.13910.01790.1288-54.7049-17.336621.2531
52.2048-0.1956-0.50860.82110.11860.62420.0555-0.10240.50130.0135-0.1125-0.2972-0.01540.3380.04230.44520.1720.05340.32270.07140.5355-44.9994-13.888766.2661
61.3710.72690.18331.64280.25641.17970.03580.02120.12860.14130.0708-0.4712-0.19630.3292-0.02430.3740.18680.01630.58790.11570.711-31.6078-29.22165.623
71.32520.2406-0.46341.3742-0.11761.54310.07810.03260.0753-0.0342-0.091-0.16220.06150.12020.02250.18740.0805-0.00990.18030.05070.1554-54.687-31.857962.5918
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 289 )A200 - 289
3X-RAY DIFFRACTION3chain 'A' and (resid 290 through 315 )A290 - 315
4X-RAY DIFFRACTION4chain 'A' and (resid 316 through 522 )A316 - 522
5X-RAY DIFFRACTION5chain 'B' and (resid 161 through 199 )B161 - 199
6X-RAY DIFFRACTION6chain 'B' and (resid 200 through 315 )B200 - 315
7X-RAY DIFFRACTION7chain 'B' and (resid 316 through 521 )B316 - 521

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