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- PDB-6a2m: Crystal structure of wild type Plasmodium falciparum DHFR-TS comp... -

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Basic information

Entry
Database: PDB / ID: 6a2m
TitleCrystal structure of wild type Plasmodium falciparum DHFR-TS complexed with BT2, 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 / mitochondrion / cytosol
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-9QR / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / PHOSPHATE ION / 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: 2.2 Å
Model detailsCrystal structure of wild type Plasmodium falciparum DHFR-TS complexed with BT2, 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)146,79810
Polymers143,6562
Non-polymers3,1428
Water12,268681
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11990 Å2
ΔGint-61 kcal/mol
Surface area47280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.480, 157.278, 165.742
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 5 types, 689 molecules

#2: Chemical ChemComp-9QR / 5-(4-{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: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 681 / 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: 2.65 Å3/Da / Density % sol: 53.64 % / Mosaicity: 0.433 °
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: Mar 27, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 77583 / % possible obs: 98.8 % / Redundancy: 4.4 % / Rmerge(I) obs: 0.034 / Χ2: 0.983 / Net I/σ(I): 20.8 / Num. measured all: 338494
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.2-2.283.40.28870070.994190.6
2.28-2.373.70.25376220.919198.7
2.37-2.484.10.18377500.923199.7
2.48-2.614.40.1377340.9421100
2.61-2.774.60.08878190.9741100
2.77-2.994.80.05677910.9471100
2.99-3.294.80.03678350.9651100
3.29-3.764.70.02478590.9961100
3.76-4.734.60.03179451.138199.9
4.73-304.40.01682211.006199.3

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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: 2.2→30 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.902 / SU B: 5.385 / SU ML: 0.137 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.256 / ESU R Free: 0.212 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2426 3635 5.1 %RANDOM
Rwork0.191 ---
obs0.1936 68337 91.84 %-
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: 40.471 Å2 / Biso min: 9.71 Å2
Baniso -1Baniso -2Baniso -3
1-0.89 Å20 Å2-0 Å2
2---0.44 Å20 Å2
3----0.45 Å2
Refinement stepCycle: final / Resolution: 2.2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8917 0 208 681 9806
Biso mean--57.57 38.11 -
Num. residues----1073
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0199345
X-RAY DIFFRACTIONr_bond_other_d0.0030.028769
X-RAY DIFFRACTIONr_angle_refined_deg1.5081.97412643
X-RAY DIFFRACTIONr_angle_other_deg0.948320163
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.61851065
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.6124.851470
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.307151662
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6671536
X-RAY DIFFRACTIONr_chiral_restr0.0850.21347
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0210411
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022295
LS refinement shellResolution: 2.202→2.259 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.317 131 -
Rwork0.24 2466 -
all-2597 -
obs--45.57 %

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