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- PDB-9elx: Crystal Structure of human cyclic GMP-AMP synthase (cGAS) in comp... -

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Basic information

Entry
Database: PDB / ID: 9elx
TitleCrystal Structure of human cyclic GMP-AMP synthase (cGAS) in complex with compound 5; 3-((2-((3-chloro-4-fluorophenyl)amino)-2-oxoethyl)carbamoyl)picolinic acid
ComponentsCyclic GMP-AMP synthase
KeywordsTRANSFERASE / human cyclic GMP-AMP synthase / AMP-PNP Compound 5
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
: / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / : / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.53 Å
AuthorsSietsema, D.V.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization.
Authors: Cyr, P. / Fader, L.D. / Burch, J.D. / Pike, K.A. / Sietsema, D.V. / Boily, M.O. / Ciblat, S. / Sgarioto, N. / Skeldon, A.M. / Gaudreault, S. / Le Gros, P. / Dumais, V. / McKay, D.J.J. / ...Authors: Cyr, P. / Fader, L.D. / Burch, J.D. / Pike, K.A. / Sietsema, D.V. / Boily, M.O. / Ciblat, S. / Sgarioto, N. / Skeldon, A.M. / Gaudreault, S. / Le Gros, P. / Dumais, V. / McKay, D.J.J. / Abraham, N.S. / Seliniotakis, R. / Beveridge, R.E.
History
DepositionDec 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2025Provider: 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)43,8336
Polymers42,8001
Non-polymers1,0335
Water3,549197
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)128.246, 51.233, 59.953
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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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: 42800.168 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CGAS, C6orf150, MB21D1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q8N884, cyclic GMP-AMP synthase

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Non-polymers , 5 types, 202 molecules

#2: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-A1BJH / 3-{[2-(3-chloro-4-fluoroanilino)-2-oxoethyl]carbamoyl}pyridine-2-carboxylic acid


Mass: 351.717 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H11ClFN3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.39 Å3/Da / Density % sol: 48.6 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: (5mg/ml) HcGAS catalytic domain was mixed with 17/16 bp dsDNA in a molar ratio of 1:1.25 protein:DNA in a buffer containing 20 mM Tris pH 7.5, 150 mM NaCl, 10mM MnCl2, 1mM TCEP, 5mM AMPPNP ...Details: (5mg/ml) HcGAS catalytic domain was mixed with 17/16 bp dsDNA in a molar ratio of 1:1.25 protein:DNA in a buffer containing 20 mM Tris pH 7.5, 150 mM NaCl, 10mM MnCl2, 1mM TCEP, 5mM AMPPNP and 1mM compound. Crystals were obtained with sitting drop vapor diffusion in drops mixed 1:1 with a reservoir of 0.1M Tris pH 8.0, 0.1 M Lithium Sulfate, 20% PEG 4000 and cGAS crystal seeds. Crystals were cryo-protected using reservoir solution supplemented with 25% ethylene glycol and flash-frozen in Liquid N2.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.979333 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Dec 13, 2018
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979333 Å / Relative weight: 1
ReflectionResolution: 1.53→47.58 Å / Num. obs: 60481 / % possible obs: 99.95 % / Redundancy: 7.2 % / Biso Wilson estimate: 21.54 Å2 / CC1/2: 0.999 / Net I/σ(I): 15.17
Reflection shellResolution: 1.53→1.585 Å / Rmerge(I) obs: 0.07744 / Num. unique obs: 60477 / Rpim(I) all: 0.03107 / Rrim(I) all: 0.0836

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
DIALSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.53→47.58 Å / SU ML: 0.1862 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 19.7591
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2001 3006 4.93 %
Rwork0.1769 57915 -
obs0.1781 60481 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.06 Å2
Refinement stepCycle: LAST / Resolution: 1.53→47.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2905 0 58 197 3160
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0143121
X-RAY DIFFRACTIONf_angle_d1.40754211
X-RAY DIFFRACTIONf_chiral_restr0.0823449
X-RAY DIFFRACTIONf_plane_restr0.0127537
X-RAY DIFFRACTIONf_dihedral_angle_d16.6873418
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.53-1.550.32531610.27012729X-RAY DIFFRACTION99.97
1.55-1.580.31421140.24922749X-RAY DIFFRACTION100
1.58-1.610.2841440.23632709X-RAY DIFFRACTION100
1.61-1.640.27751370.22392698X-RAY DIFFRACTION100
1.64-1.670.27951380.21852744X-RAY DIFFRACTION99.97
1.67-1.710.24071280.20072755X-RAY DIFFRACTION100
1.71-1.750.2181470.19152696X-RAY DIFFRACTION99.96
1.75-1.790.22471480.18642739X-RAY DIFFRACTION99.97
1.79-1.840.2121360.18842732X-RAY DIFFRACTION100
1.84-1.890.22681560.19652707X-RAY DIFFRACTION99.97
1.89-1.950.23441690.19892708X-RAY DIFFRACTION100
1.95-2.020.22331410.1832740X-RAY DIFFRACTION100
2.02-2.110.19121290.17542755X-RAY DIFFRACTION100
2.11-2.20.22341590.16872753X-RAY DIFFRACTION100
2.2-2.320.21421360.17252769X-RAY DIFFRACTION100
2.32-2.460.2131320.17862771X-RAY DIFFRACTION99.97
2.46-2.650.19181530.18322742X-RAY DIFFRACTION99.93
2.65-2.920.21051400.18232794X-RAY DIFFRACTION100
2.92-3.340.2091530.17472799X-RAY DIFFRACTION99.83
3.34-4.210.17881420.15542831X-RAY DIFFRACTION99.8
4.21-47.580.14911430.16332995X-RAY DIFFRACTION99.71
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)
11.456681204190.826536814608-0.3039546931761.37757963077-0.5441021201452.922647612470.107868809724-0.3166525232910.05908320152760.161288503422-0.1349453935460.0167509038005-0.0245594198020.1820699628410.02614996644790.169085030396-0.0157891570783-0.007509463317950.205569822120.01429516570.172276231806-8.2475812366220.7339420041-11.4059541957
21.415520666980.8411943112730.4395508526482.073373378610.3841381159894.007101876680.39854661634-0.602493703059-0.1332002558810.767953744626-0.3382604055960.08033780974960.906813233775-0.5075735480170.01528698649330.419451577223-0.1342042081650.003489763745210.3622458623880.05649522311240.274464792067-23.68791938490.6939858538212.62549821045
32.51069969529-0.217383805547-0.6665878106664.24004956534-0.1865710095793.146942137010.148201520056-0.4083682297730.4232848088230.257736591839-0.04530712715610.241713766354-0.437951955051-0.0673382257-0.07570480483990.253201163168-0.03527535832640.02870832970150.363273243362-0.05933766746210.226489415028-17.171590203722.3145680366-0.145381243888
42.32903514888-0.148163627299-1.188628247882.019001466311.000057852813.148902037710.0367542997059-0.209189037654-0.1532781477610.150290764025-0.08675945554060.1078257787370.131750765069-0.1207132907710.1015251420690.149387084798-0.00722159781277-0.01825816964840.1521222269730.06089034251620.175854204167-16.91849019051.65302974334-11.6018769371
51.75026647661-0.4753124963510.6822738483561.62136142229-0.673258286661.126904892220.01641888937960.07479940202260.1166634776-0.0489152306654-0.04786883222260.00989843857334-0.002668325797010.04903131547170.01548159082010.177907295744-0.00512401684182-0.01501832931440.101924769738-0.002129341322630.142462765127-16.992246972413.1740007922-29.0704839537
62.09586289588-1.141157441470.7044076924753.85325366604-2.977156470094.245298545710.0743342605972-0.004951393648450.0341535653272-0.004758013265550.05039330110440.304507569321-0.135761533206-0.153454250628-0.2053071385220.157523297159-0.00721613815365-0.02515356252470.102423319175-0.04623336859860.168426159727-28.215008564713.9111296604-27.476647977
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 162 through 233 )162 - 2331 - 72
22chain 'A' and (resid 234 through 272 )234 - 27273 - 104
33chain 'A' and (resid 273 through 326 )273 - 326105 - 158
44chain 'A' and (resid 327 through 387 )327 - 387159 - 219
55chain 'A' and (resid 388 through 477 )388 - 477220 - 309
66chain 'A' and (resid 478 through 522 )478 - 522310 - 354

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