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- PDB-7kxs: Computational design of constitutively active cGAS -

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Basic information

Entry
Database: PDB / ID: 7kxs
TitleComputational design of constitutively active cGAS
ComponentsCyclic GMP-AMP synthase
KeywordsDE NOVO PROTEIN / DE NOVO DESIGNED / constitutive mutant / cGAS
Function / homology
Function and homology information


regulation of type I interferon production / cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / negative regulation of DNA repair / cGAS/STING signaling pathway / regulation of immunoglobulin production / regulation of T cell activation / pattern recognition receptor signaling pathway ...regulation of type I interferon production / cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / negative regulation of DNA repair / cGAS/STING signaling pathway / regulation of immunoglobulin production / regulation of T cell activation / pattern recognition receptor signaling pathway / negative regulation of double-strand break repair via homologous recombination / negative regulation of cGAS/STING signaling pathway / cellular response to exogenous dsRNA / cytoplasmic pattern recognition receptor signaling pathway / cGMP-mediated signaling / cAMP-mediated signaling / nucleosome binding / positive regulation of type I interferon production / regulation of immune response / positive regulation of defense response to virus by host / phosphatidylinositol-4,5-bisphosphate binding / activation of innate immune response / molecular condensate scaffold activity / determination of adult lifespan / positive regulation of cellular senescence / site of double-strand break / double-stranded DNA binding / defense response to virus / nuclear body / DNA repair / innate immune response / 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-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21
Similarity search - Domain/homology
Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsDowling, Q. / Volkman, H.E. / Gray, E.E. / Ovchinnikov, S. / Cambier, S. / Bera, A.K. / Bick, M. / Kang, A. / Stetson, D.B. / King, N.P.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates Foundation United States
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2023
Title: Computational design of constitutively active cGAS.
Authors: Dowling, Q.M. / Volkman, H.E. / Gray, E.E. / Ovchinnikov, S. / Cambier, S. / Bera, A.K. / Sankaran, B. / Johnson, M.R. / Bick, M.J. / Kang, A. / Stetson, D.B. / King, N.P.
History
DepositionDec 4, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 21, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)84,9594
Polymers84,8282
Non-polymers1312
Water64936
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.023, 109.349, 77.004
Angle α, β, γ (deg.)90.000, 91.364, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Cyclic GMP-AMP synthase / / m-cGAS / 2'3'-cGAMP synthase / Mab-21 domain-containing protein 1


Mass: 42414.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Mus musculus (house mouse) / References: UniProt: Q8C6L5, cyclic GMP-AMP synthase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 36 / 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: 2.38 Å3/Da / Density % sol: 48.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 20 % w/v Polyethylene glycol 3,350 200 mM Potassium thiocyanate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→48.01 Å / Num. obs: 24481 / % possible obs: 99.6 % / Redundancy: 3.7 % / Biso Wilson estimate: 66.3 Å2 / CC1/2: 0.993 / CC star: 0.998 / Rmerge(I) obs: 0.1081 / Net I/σ(I): 7.17
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 3.4 % / Rmerge(I) obs: 1.283 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 2421 / CC1/2: 0.653 / CC star: 0.889 / % possible all: 97.12

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house model

Resolution: 2.6→48.01 Å / SU ML: 0.4031 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.991
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2614 2007 8.21 %
Rwork0.2088 22431 -
obs0.2132 24438 99.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 85.8 Å2
Refinement stepCycle: LAST / Resolution: 2.6→48.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5727 0 2 37 5766
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00185848
X-RAY DIFFRACTIONf_angle_d0.56987848
X-RAY DIFFRACTIONf_chiral_restr0.0383849
X-RAY DIFFRACTIONf_plane_restr0.0031990
X-RAY DIFFRACTIONf_dihedral_angle_d12.58862279
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.670.36541510.33791574X-RAY DIFFRACTION96.21
2.67-2.740.39341390.32941556X-RAY DIFFRACTION99.82
2.74-2.820.31911380.29481619X-RAY DIFFRACTION99.94
2.82-2.910.30631350.28971605X-RAY DIFFRACTION99.94
2.91-3.010.33621410.29051602X-RAY DIFFRACTION99.89
3.01-3.130.31251420.26821583X-RAY DIFFRACTION99.88
3.13-3.280.30291390.2421611X-RAY DIFFRACTION100
3.28-3.450.2941470.23231613X-RAY DIFFRACTION99.94
3.45-3.660.25671480.21771603X-RAY DIFFRACTION100
3.66-3.950.27211430.19981605X-RAY DIFFRACTION100
3.95-4.340.20591420.17381606X-RAY DIFFRACTION100
4.34-4.970.23411450.1641607X-RAY DIFFRACTION100
4.97-6.260.23111460.19351613X-RAY DIFFRACTION99.83
6.26-48.010.24851510.18111634X-RAY DIFFRACTION99.28
Refinement TLS params.Method: refined / Origin x: -7.57300421242 Å / Origin y: -5.99455211287 Å / Origin z: 17.9138206495 Å
111213212223313233
T0.329766393065 Å2-0.0427728451656 Å2-0.00927100215159 Å2-0.357345813015 Å20.0459164943879 Å2--0.388472705741 Å2
L0.505354248953 °2-0.16972326929 °2-0.0331551492384 °2-0.498223527905 °20.315844901736 °2--0.876537825441 °2
S0.0308596035087 Å °0.0927484563571 Å °0.0194159860123 Å °0.0685861727934 Å °-0.0286009923054 Å °0.00834704975884 Å °0.0916043968986 Å °-0.0209975805215 Å °-1.94145018256E-6 Å °
Refinement TLS groupSelection details: all

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