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- PDB-6aoi: Crystal structure of Toxoplasma gondii TS-DHFR complexed with NAD... -

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Basic information

Entry
Database: PDB / ID: 6aoi
TitleCrystal structure of Toxoplasma gondii TS-DHFR complexed with NADPH, dUMP, PDDF, and 5-(4-phenylpiperazin-1-yl)-6-propylpyrimidine-2,4-diamine (TRC-2528)
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / Toxoplasma gondii / Pyrimethamine / DHFR
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
Similarity search - Function
Bifunctional dihydrofolate reductase/thymidylate synthase / Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / 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/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / 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 domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-BOJ / 10-PROPARGYL-5,8-DIDEAZAFOLIC ACID / 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: 2.97 Å
AuthorsThomas, S.B. / Li, Y. / Chen, Z. / Lu, H.
CitationJournal: To Be Published
Title: Identification of selective, brain penetrant Toxoplasma gondii dihydrofolate reductase inhibitors for the treatment of toxoplasmosis
Authors: Thomas, S.B. / Hopper, A.
History
DepositionAug 16, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 22, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bifunctional dihydrofolate reductase-thymidylate synthase
B: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,11610
Polymers128,4292
Non-polymers3,6878
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12270 Å2
ΔGint-55 kcal/mol
Surface area39860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.437, 145.053, 174.503
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 64214.312 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Production host: Escherichia coli (E. coli)
References: UniProt: Q07422, dihydrofolate reductase, thymidylate synthase
#2: Chemical ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP / Deoxyuridine monophosphate


Mass: 308.182 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C9H13N2O8P
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C21H30N7O17P3
#4: Chemical ChemComp-CB3 / 10-PROPARGYL-5,8-DIDEAZAFOLIC ACID


Mass: 477.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C24H23N5O6
#5: Chemical ChemComp-BOJ / 5-(4-phenylpiperazin-1-yl)-6-propylpyrimidine-2,4-diamine


Mass: 312.413 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H24N6

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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: 2.47 Å3/Da / Density % sol: 50.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.8 / Details: 0.2 M ammonium citrate, pH 4.6, 15% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.979282 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 26, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979282 Å / Relative weight: 1
ReflectionResolution: 2.97→50 Å / Num. obs: 26892 / % possible obs: 91.7 % / Redundancy: 2.7 % / Rmerge(I) obs: 0.114 / Net I/σ(I): 9.8
Reflection shellResolution: 2.97→3.08 Å / Rmerge(I) obs: 0.596

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Processing

Software
NameVersionClassification
REFMAC5.6.0016refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
Blu-Icedata collection
HKL-2000data extraction
HKL-2000data processing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4EIL

4eil


Resolution: 2.97→50 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.886 / Cross valid method: THROUGHOUT / ESU R Free: 0.49
RfactorNum. reflection% reflectionSelection details
Rfree0.27557 1271 4.7 %RANDOM
Rwork0.21732 ---
obs0.22006 25595 89.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 83.287 Å2
Baniso -1Baniso -2Baniso -3
1--4.99 Å20 Å2-0 Å2
2---6.17 Å20 Å2
3---11.16 Å2
Refinement stepCycle: 1 / Resolution: 2.97→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8172 0 252 0 8424
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0198672
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1351.98611780
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.19751018
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.46323.191398
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.921151421
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7631568
X-RAY DIFFRACTIONr_chiral_restr0.0710.21271
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0216606
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.668.1914099
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.50412.2675108
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.9798.3784573
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined9.1268.2213021
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.93→3.006 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.365 63 -
Rwork0.373 1234 -
obs--59.47 %

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