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- PDB-7fgw: Toxoplasma gondii dihydrofolate reductase thymidylate synthase (T... -

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Basic information

Entry
Database: PDB / ID: 7fgw
TitleToxoplasma gondii dihydrofolate reductase thymidylate synthase (TgDHFR-TS) complexed with pyrimethamine, NADPH and dUMP
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / Pyrimethamine / Toxoplasma gondii / dihydrofolate reductase / thymidylate synthase
Function / homology
Function and homology information


thymidylate synthase / thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / mitochondrion / cytosol
Similarity search - Function
Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase ...Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase-like domain superfamily / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
BENZAMIDINE / Chem-CP6 / Chem-NDP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesToxoplasma gondii (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsVanichtanankul, J. / Yoomuang, A. / Taweechai, S. / Saeyang, T. / Yuvaniyama, Y. / Tarnchompoo, B. / Yuthavong, Y. / Kamchonwongpaisan, S.
Funding support Thailand, 1items
OrganizationGrant numberCountry
The Thailand Research Fund (TRF)TRG5780138 Thailand
CitationJournal: Acs Chem.Biol. / Year: 2022
Title: Structural Insight into Effective Inhibitors' Binding to Toxoplasma gondii Dihydrofolate Reductase Thymidylate Synthase.
Authors: Vanichtanankul, J. / Yoomuang, A. / Taweechai, S. / Saeyang, T. / Pengon, J. / Yuvaniyama, J. / Tarnchompoo, B. / Yuthavong, Y. / Kamchonwongpaisan, S.
History
DepositionJul 28, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 29, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 6, 2022Group: Derived calculations
Category: pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Item: _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.value
Revision 1.2Jul 27, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 29, 2023Group: 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: Bifunctional dihydrofolate reductase-thymidylate synthase
B: Bifunctional dihydrofolate reductase-thymidylate synthase
C: Bifunctional dihydrofolate reductase-thymidylate synthase
D: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)280,82018
Polymers275,3714
Non-polymers5,45014
Water27,5811531
1
A: Bifunctional dihydrofolate reductase-thymidylate synthase
B: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,4109
Polymers137,6852
Non-polymers2,7257
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7230 Å2
ΔGint-43 kcal/mol
Surface area47670 Å2
MethodPISA
2
C: Bifunctional dihydrofolate reductase-thymidylate synthase
D: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,4109
Polymers137,6852
Non-polymers2,7257
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7350 Å2
ΔGint-45 kcal/mol
Surface area47670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.282, 101.121, 107.208
Angle α, β, γ (deg.)85.450, 83.700, 84.250
Int Tables number1
Space group name H-MP1
Space group name HallP1

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Bifunctional dihydrofolate reductase-thymidylate synthase / DHFR-TS


Mass: 68842.656 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q07422, dihydrofolate reductase, thymidylate synthase

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Non-polymers , 5 types, 1545 molecules

#2: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical
ChemComp-CP6 / 5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE / PYRIMETHAMINE


Mass: 248.711 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H13ClN4 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antiparasitic*YM
#4: Chemical ChemComp-BEN / BENZAMIDINE


Mass: 120.152 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H8N2
#5: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H13N2O8P
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1531 / 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: 2.77 Å3/Da / Density % sol: 55.57 %
Crystal growTemperature: 297 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.2 M Lithium nitrate, 14% (w/v) PEG4000, 0.1 M Bis-Tris propane pH 7.5 and 1% (w/v) benzamidine hydrochloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13B1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 24, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→30 Å / Num. obs: 152902 / % possible obs: 96.3 % / Redundancy: 2.2 % / Biso Wilson estimate: 25.68 Å2 / Rmerge(I) obs: 0.031 / Net I/σ(I): 25.3
Reflection shellResolution: 2.15→2.23 Å / Redundancy: 2 % / Rmerge(I) obs: 0.243 / Num. unique obs: 14023 / % possible all: 88.3

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
PHASERphasing
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EIL

4eil


Resolution: 2.15→29.29 Å / SU ML: 0.2316 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 22.0867
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2087 6942 4.99 %
Rwork0.16 132229 -
obs0.1624 139171 87.16 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 31.82 Å2
Refinement stepCycle: LAST / Resolution: 2.15→29.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17839 0 358 1531 19728
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008618647
X-RAY DIFFRACTIONf_angle_d0.99825295
X-RAY DIFFRACTIONf_chiral_restr0.05742728
X-RAY DIFFRACTIONf_plane_restr0.00963266
X-RAY DIFFRACTIONf_dihedral_angle_d15.80896923
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.180.26461230.19292392X-RAY DIFFRACTION47.43
2.18-2.20.25111690.18812957X-RAY DIFFRACTION59.23
2.2-2.230.25621970.18633108X-RAY DIFFRACTION61.47
2.23-2.260.27481690.20153216X-RAY DIFFRACTION64.49
2.26-2.290.24951730.20033489X-RAY DIFFRACTION68
2.29-2.320.25061840.18053602X-RAY DIFFRACTION71.23
2.32-2.350.25381980.18193750X-RAY DIFFRACTION73.78
2.35-2.390.25892100.18863824X-RAY DIFFRACTION76.62
2.39-2.430.23311940.19314029X-RAY DIFFRACTION79.81
2.43-2.470.23962370.1914236X-RAY DIFFRACTION82.91
2.47-2.510.24672240.18754345X-RAY DIFFRACTION86.57
2.51-2.550.23682270.1844643X-RAY DIFFRACTION90.09
2.55-2.60.24952760.18664655X-RAY DIFFRACTION93.6
2.6-2.660.2322700.1874884X-RAY DIFFRACTION96.26
2.66-2.710.24722520.18844888X-RAY DIFFRACTION97.05
2.71-2.780.262730.18124889X-RAY DIFFRACTION97.56
2.78-2.850.23372640.18464972X-RAY DIFFRACTION97.34
2.85-2.920.24282620.18464861X-RAY DIFFRACTION97.43
2.92-3.010.25913030.17824970X-RAY DIFFRACTION97.79
3.01-3.110.23622580.17144912X-RAY DIFFRACTION97.55
3.11-3.220.24232620.16984935X-RAY DIFFRACTION97.58
3.22-3.350.20782250.16644955X-RAY DIFFRACTION97.7
3.35-3.50.20412650.15574910X-RAY DIFFRACTION96.91
3.5-3.680.1752590.14464901X-RAY DIFFRACTION97.23
3.68-3.910.22330.14364974X-RAY DIFFRACTION97.67
3.91-4.210.16952320.13394985X-RAY DIFFRACTION97.68
4.21-4.630.14182490.11584925X-RAY DIFFRACTION97.44
4.64-5.30.1722550.12994977X-RAY DIFFRACTION98.24
5.3-6.670.18632450.15955043X-RAY DIFFRACTION99.32
6.67-29.290.15552540.13865002X-RAY DIFFRACTION98.72

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