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

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Basic information

Entry
Database: PDB / ID: 7ftw
TitleCrystal Structure of human cyclic GMP-AMP synthase in complex with 5-bromo-2-hydroxy-N-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]benzamide
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
: / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.208 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)42,8573
Polymers42,4051
Non-polymers4522
Water50428
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)45.294, 59.266, 162.222
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-YPL / 5-bromo-2-hydroxy-N-{[(3M)-3-(1-methyl-1H-pyrazol-4-yl)phenyl]methyl}benzamide


Mass: 386.243 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16BrN3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 2.57 Å3/Da / Density % sol: 52.09 %
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: 0.9999 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Dec 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.21→81.11 Å / Num. obs: 22784 / % possible obs: 99.9 % / Redundancy: 6.48 % / Biso Wilson estimate: 70.496 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.054 / Rrim(I) all: 0.058 / Χ2: 0.857 / Net I/σ(I): 16.49 / Num. measured all: 147647 / Scaling rejects: 7
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
2.21-2.276.6392.4730.7111127167716760.3242.68399.9
2.27-2.336.6131.8011.0310415157515750.4471.955100
2.33-2.396.2231.3521.319926159615950.5731.47699.9
2.39-2.476.3131.0581.689526150915090.7051.154100
2.47-2.556.8630.7352.5810068146814670.8380.79699.9
2.55-2.646.8510.5263.589900144514450.9160.569100
2.64-2.746.7620.4054.679278137413720.940.43899.9
2.74-2.856.6750.2986.079051135613560.9660.324100
2.85-2.986.6110.1999.098422127412740.9850.216100
2.98-3.126.1160.13712.567516122912290.9910.15100
3.12-3.296.5060.09717.737664117811780.9960.105100
3.29-3.496.7970.06525.117599112111180.9980.07199.7
3.49-3.736.7180.05133.017087105610550.9990.05599.9
3.73-4.036.5220.04138.0963079699670.9990.04599.8
4.03-4.426.1240.03244.5855619119080.9990.03599.7
4.42-4.945.940.02847.9750318488470.9990.03199.9
4.94-5.76.4740.02950.3148107437430.9990.031100
5.7-6.986.0920.02948.5638446316310.9990.032100
6.98-9.875.3510.02155.12278852152110.024100
9.87-59.2665.4310.01960.317273223180.9990.0298.8

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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: 2.208→59.266 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 34.4 / Stereochemistry target values: ML
Details: ligand well defined by electron density. Has different conformation compared to others from same series.
RfactorNum. reflection% reflectionSelection details
Rfree0.2608 1014 5.15 %RANDOM
Rwork0.2116 18665 --
obs0.2142 19679 86.55 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 199.36 Å2 / Biso mean: 84.9179 Å2 / Biso min: 34.57 Å2
Refinement stepCycle: final / Resolution: 2.208→59.266 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2905 0 25 28 2958
Biso mean--75.36 62.76 -
Num. residues----352
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2085-2.32490.3518430.328368973223
2.3249-2.47060.41441340.30982469260381
2.4706-2.66130.34821660.285930483214100
2.6613-2.92910.30241590.273830253184100
2.9291-3.3530.29821610.243930683229100
3.353-4.22420.25641910.203330943285100
4.2242-59.28730.21291600.174532723432100
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)
14.30692.569-0.57492.29510.22823.2993-0.1225-1.1098-0.6641-0.1188-0.1992-1.1127-0.21090.85540.23220.50330.00690.02260.7880.05250.532633.217111.866224.9469
23.9722-1.27560.35765.4413-0.02655.4812-0.1727-0.3329-1.64330.00620.05260.46210.6865-0.05570.17740.5702-0.05690.17360.57950.23661.027615.0205-2.593622.1331
36.5973-0.1724-0.44129.23961.08337.1883-0.3408-1.8783-1.36141.23010.10280.10780.55820.62840.21140.81330.0910.0151.09280.38220.83926.6072-0.096435.1989
44.80521.6565-2.09463.0363-0.3072.0657-0.13830.1358-0.7439-0.22460.08150.52110.3698-0.59930.09550.33470.00380.02420.4712-0.04130.520811.77218.566314.2192
53.84030.7094-0.81353.06870.79176.58150.2634-0.39940.55790.2043-0.03490.1748-0.98160.0951-0.23570.46490.05380.01770.3679-0.09240.385219.583225.604720.0417
65.00121.252-0.11276.88752.18656.82710.397-0.99080.60510.8775-0.29350.2045-0.8578-0.6924-0.06550.66160.13410.08430.6875-0.1760.484411.177925.918829.5367
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 161 through 198 )A161 - 198
2X-RAY DIFFRACTION2chain 'A' and (resid 199 through 289 )A199 - 289
3X-RAY DIFFRACTION3chain 'A' and (resid 290 through 315 )A290 - 315
4X-RAY DIFFRACTION4chain 'A' and (resid 316 through 379 )A316 - 379
5X-RAY DIFFRACTION5chain 'A' and (resid 380 through 477 )A380 - 477
6X-RAY DIFFRACTION6chain 'A' and (resid 478 through 522 )A478 - 522

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