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- PDB-6a2k: Crystal structure of wild type Plasmodium falciparum DHFR-TS comp... -

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Basic information

Entry
Database: PDB / ID: 6a2k
TitleCrystal structure of wild type Plasmodium falciparum DHFR-TS complexed with BT1, NADPH, and dUMP
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / Rossmann fold / Dual-binding Inhibitor
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
Similarity search - Function
Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #2210 / 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 ...Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #2210 / 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 / Single alpha-helices involved in coiled-coils or other helix-helix interfaces / Dihydrofolate reductase-like domain superfamily / Helix non-globular / Special / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-9QO / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
Model detailsCrystal structure of wild type Plasmodium falciparum DHFR-TS complexed with BT1, NADPH, and dUMP
AuthorsChitnumsub, P. / Jaruwat, A. / Tarnchampoo, B. / Yuthavong, Y.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates Foundation52992 United States
CitationJournal: ACS Med Chem Lett / Year: 2018
Title: Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance.
Authors: Tarnchompoo, B. / Chitnumsub, P. / Jaruwat, A. / Shaw, P.J. / Vanichtanankul, J. / Poen, S. / Rattanajak, R. / Wongsombat, C. / Tonsomboon, A. / Decharuangsilp, S. / Anukunwithaya, T. / ...Authors: Tarnchompoo, B. / Chitnumsub, P. / Jaruwat, A. / Shaw, P.J. / Vanichtanankul, J. / Poen, S. / Rattanajak, R. / Wongsombat, C. / Tonsomboon, A. / Decharuangsilp, S. / Anukunwithaya, T. / Arwon, U. / Kamchonwongpaisan, S. / Yuthavong, Y.
History
DepositionJun 12, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 24, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 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)146,6088
Polymers143,6562
Non-polymers2,9526
Water6,323351
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11800 Å2
ΔGint-46 kcal/mol
Surface area46840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.287, 154.246, 163.624
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Bifunctional dihydrofolate reductase-thymidylate synthase


Mass: 71828.000 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: DHFR-TS, dhfr-ts / Plasmid: pET17b / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: A7UD81
#2: Chemical ChemComp-9QO / 5-(3-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)-6-ethylpyrimidine-2,4-diamine


Mass: 424.499 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N8O2
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#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.: 351 / Source method: isolated from a natural source / Formula: H2O

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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: 50.25 % / Mosaicity: 0.878 °
Crystal growTemperature: 297 K / Method: microbatch / pH: 4.5 / Details: PEG 4000, NH4OAc

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13B1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 4, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.38→30 Å / Num. obs: 57573 / % possible obs: 98.4 % / Redundancy: 5.3 % / Rmerge(I) obs: 0.066 / Χ2: 1.35 / Net I/σ(I): 15.9 / Num. measured all: 307306
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.38-2.4750.33756751.173198.4
2.47-2.565.30.27357511.214199.9
2.56-2.685.40.21857771.336199.9
2.68-2.825.50.16857671.375199.9
2.82-35.50.13157621.466199.8
3-3.235.50.09657751.56199.4
3.23-3.555.40.06857221.517198.2
3.55-4.075.30.05456991.473196.9
4.07-5.125.10.0556291.387194.7
5.12-305.50.04160161.006197.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data scaling
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1J3I

1j3i


Resolution: 2.38→27.83 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.917 / SU B: 6.723 / SU ML: 0.162 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.353 / ESU R Free: 0.252 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2481 2902 5.1 %RANDOM
Rwork0.1917 ---
obs0.1946 54239 97.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 120 Å2 / Biso mean: 53.655 Å2 / Biso min: 23.17 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å20 Å20 Å2
2--1.57 Å2-0 Å2
3----1.49 Å2
Refinement stepCycle: final / Resolution: 2.38→27.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8880 0 198 351 9429
Biso mean--75.32 44.39 -
Num. residues----1070
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0199297
X-RAY DIFFRACTIONr_angle_refined_deg1.6961.97512575
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.31751060
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.44124.806464
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.201151656
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9031536
X-RAY DIFFRACTIONr_chiral_restr0.1150.21343
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0216979
LS refinement shellResolution: 2.375→2.436 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.297 200 -
Rwork0.21 3875 -
all-4075 -
obs--96.86 %

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