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- PDB-8jfb: V1/S quadruple mutant Plasmodium falciparum dihydrofolate reducta... -

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Basic information

Entry
Database: PDB / ID: 8jfb
TitleV1/S quadruple mutant Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with compound 4 (B21588), NADPH and dUMP
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / DHFR / dihydrofolate reductase / Plasmodium falciparum / malaria
Function / homology
Function and homology information


thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / nucleotide binding / mitochondrion / cytosol
Similarity search - Function
Bifunctional dihydrofolate reductase/thymidylate synthase / 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 ...Bifunctional dihydrofolate reductase/thymidylate synthase / 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 / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-NDP / Chem-U86 / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsVanichtanankul, J. / Saeyang, T. / Vitsupakorn, D. / Saepua, S. / Thongpanchang, C. / Yuthavong, Y. / Kamchonwongpaisan, S. / Hoarau, M.
Funding support Thailand, 1items
OrganizationGrant numberCountry
National Center for Genetic Engineering and Biotechnology (Thailand)P1850116 Thailand
CitationJournal: Rsc Med Chem / Year: 2023
Title: Discovery of rigid biphenyl Plasmodium falciparum DHFR inhibitors using a fragment linking strategy.
Authors: Hoarau, M. / Sermmai, P. / Varatthan, T. / Thiabma, R. / Jantra, T. / Rattanajak, R. / Vitsupakorn, D. / Vanichtanankul, J. / Saepua, S. / Yuthavong, Y. / Thongpanchang, C. / Kamchonwongpaisan, S.
History
DepositionMay 17, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 23, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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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)146,6208
Polymers143,8162
Non-polymers2,8046
Water5,134285
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11700 Å2
ΔGint-48 kcal/mol
Surface area44430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.777, 156.233, 167.051
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 71908.133 Da / Num. of mol.: 2 / Mutation: N51I, C59R, S108N, I164L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: DHFR-TS, V1/S / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: D9N170
#2: Chemical ChemComp-U86 / 3-[4-[[2,4-bis(azanyl)-6-ethyl-pyrimidin-5-yl]methyl]phenyl]benzoic acid


Mass: 348.398 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#4: Chemical ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H13N2O8P
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 285 / 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: 3.03 Å3/Da / Density % sol: 59.37 %
Crystal growTemperature: 297 K / Method: microbatch / Details: PEG3350, Sodium malonate, pH5.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: Cu FINE FOCUS / Wavelength: 1.5418 Å
DetectorType: BRUKER PHOTON 100 / Detector: CMOS / Date: Mar 23, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.65→16.32 Å / Num. obs: 41800 / % possible obs: 93.15 % / Redundancy: 2.82 % / Biso Wilson estimate: 34.14 Å2 / Rmerge(I) obs: 0.114 / Net I/σ(I): 8.38
Reflection shellResolution: 2.65→2.75 Å / Rmerge(I) obs: 0.3949 / Mean I/σ(I) obs: 2.05 / Num. unique obs: 2143

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Processing

Software
NameVersionClassification
PROTEUM PLUS4data collection
PHENIX1.20.1_4487refinement
Cootmodel building
REFMAC5refinement
PHENIXphasing
PROTEUM4data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DP3

4dp3


Resolution: 2.65→16.32 Å / SU ML: 0.3782 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 28.5555
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2801 2143 5.13 %
Rwork0.2114 39657 -
obs0.215 41800 93.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.96 Å2
Refinement stepCycle: LAST / Resolution: 2.65→16.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8776 0 188 285 9249
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00859182
X-RAY DIFFRACTIONf_angle_d1.010712427
X-RAY DIFFRACTIONf_chiral_restr0.05711332
X-RAY DIFFRACTIONf_plane_restr0.00741559
X-RAY DIFFRACTIONf_dihedral_angle_d16.43943392
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.65-2.710.34791200.26322664X-RAY DIFFRACTION95.97
2.71-2.780.32521410.25042732X-RAY DIFFRACTION97.85
2.78-2.850.31941430.25732738X-RAY DIFFRACTION98.6
2.85-2.940.31691540.24572732X-RAY DIFFRACTION98
2.94-3.030.32411390.25462754X-RAY DIFFRACTION97.47
3.03-3.140.35291520.2552647X-RAY DIFFRACTION96.19
3.14-3.260.33511400.23622662X-RAY DIFFRACTION94.79
3.26-3.410.29441600.23432616X-RAY DIFFRACTION93.06
3.41-3.590.25791260.22542546X-RAY DIFFRACTION91.07
3.59-3.810.29261290.21832580X-RAY DIFFRACTION90.6
3.81-4.10.26431330.20722496X-RAY DIFFRACTION88.88
4.1-4.510.28911420.17542484X-RAY DIFFRACTION87.59
4.51-5.140.22731390.16672539X-RAY DIFFRACTION89.27
5.14-6.410.26111780.19062640X-RAY DIFFRACTION91.85
6.41-16.320.20421470.16732827X-RAY DIFFRACTION94.17

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