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- PDB-4dph: Quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum di... -

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Basic information

Entry
Database: PDB / ID: 4dph
TitleQuadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with P65 and NADPH
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / TRANSFERASE / Plasmodium falciparum / antifolate / Rossmann fold / Reductase / NADPH binding
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/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / 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/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. / 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
BETA-MERCAPTOETHANOL / Chem-NDP / Chem-P65 / PHOSPHATE ION / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.38 Å
AuthorsYuthavong, Y. / Vilaivan, T. / Kamchonwongpaisan, S. / Charman, S.A. / McLennan, D.N. / White, K.L. / Vivas, L. / Bongard, E. / Chitnumsub, P. / Tarnchompoo, B. ...Yuthavong, Y. / Vilaivan, T. / Kamchonwongpaisan, S. / Charman, S.A. / McLennan, D.N. / White, K.L. / Vivas, L. / Bongard, E. / Chitnumsub, P. / Tarnchompoo, B. / Thongphanchang, C. / Taweechai, S. / Vanichtanakul, J. / Arwon, U. / Fantauzzi, P. / Yuvaniyama, J. / Charman, W.N. / Matthews, D.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2012
Title: Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target
Authors: Yuthavong, Y. / Tarnchompoo, B. / Vilaivan, T. / Chitnumsub, P. / Kamchonwongpaisan, S. / Charman, S.A. / McLennan, D.N. / White, K.L. / Vivas, L. / Bongard, E. / Thongphanchang, C. / ...Authors: Yuthavong, Y. / Tarnchompoo, B. / Vilaivan, T. / Chitnumsub, P. / Kamchonwongpaisan, S. / Charman, S.A. / McLennan, D.N. / White, K.L. / Vivas, L. / Bongard, E. / Thongphanchang, C. / Taweechai, S. / Vanichtanankul, J. / Rattanajak, R. / Arwon, U. / Fantauzzi, P. / Yuvaniyama, J. / Charman, W.N. / Matthews, D.
History
DepositionFeb 13, 2012Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Nov 14, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,56512
Polymers143,8162
Non-polymers2,74910
Water7,891438
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11600 Å2
ΔGint-53 kcal/mol
Surface area46910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.951, 156.447, 164.653
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: 71908.133 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Strain: V1/S / Gene: DHFR-TS / Plasmid: pET17b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: D9N170, dihydrofolate reductase, thymidylate synthase

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Non-polymers , 5 types, 448 molecules

#2: Chemical ChemComp-P65 / 2,4-diamino-6-methyl-5-[3-(2,4,5-trichlorophenoxy)propyloxy]pyrimidine


Mass: 377.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H15Cl3N4O2
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#4: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#5: Chemical
ChemComp-BME / BETA-MERCAPTOETHANOL / 2-Mercaptoethanol


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 438 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence details1. THE QUADRUPLE MUTATIONS (N51I, C59R, S108N, I164L) OF DHFR-TS IS FOUND IN PLASMODIUM FALCIPARUM ...1. THE QUADRUPLE MUTATIONS (N51I, C59R, S108N, I164L) OF DHFR-TS IS FOUND IN PLASMODIUM FALCIPARUM STRAIN V1/S. 2. THE ENTIRE PROTEIN (REDUCTASE DOMAIN: RESIDUES 1-231; SYNTHASE DOMAIN: RESIDUES 283-608) WAS EXPRESSED IN ONE POLYPEPTIDE CHAIN. SINCE THE DENSITY OF THE JUNCTION PEPTIDES (RESIDUES 232-282) BETWEEN THE TWO DOMAINS ARE NOT VISIBLE FOR BOTH MONOMERS, THERE IS STILL AMBIGUITY REGARDING HOW THE TWO DOMAINS ARE PHYSIOLOGICALLY CONNECTED, HENCE A(1-231)-A(283-608) AND B(1-231)-B(283-608), OR ANOTHER CASE, A(1-231)-B(283-608) AND B(1-231)-A(283-608).

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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: 2.59 Å3/Da / Density % sol: 52.6 % / Mosaicity: 0.49 °
Crystal growTemperature: 297 K / Method: microbatch / pH: 4.5
Details: PEG4000, NH4OAc, pH 4.5, Microbatch, temperature 297K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: Cu FINE FOCUS / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Dec 22, 2004 / Details: mirrors
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.38→56.71 Å / Num. obs: 60551 / % possible obs: 95.8 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 1.73 % / Biso Wilson estimate: 49.8 Å2 / Rmerge(I) obs: 0.055 / Χ2: 1.35 / Net I/σ(I): 6.9 / Scaling rejects: 1453
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2Rejects% possible all
2.38-2.471.710.2921653596851.02883.3
2.47-2.561.720.2622.319263111931.08996.5
2.56-2.681.720.2252.719374112231.231596.8
2.68-2.821.720.1823.219451112671.373797
2.82-31.730.1523.919627113021.514497.2
3-3.231.740.1165.119690112991.677797.4
3.23-3.561.730.0747.619603112371.7212297.3
3.56-4.071.740.04910.719806113321.5912297.7
4.07-5.131.730.0314.619965113291.3136397.7
5.13-56.711.730.02216.420068112170.9265696.7

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Processing

Software
NameVersionClassificationNB
d*TREK7.1SSIdata scaling
d*TREK7.1SSIdata reduction
REFMAC5.5.0109refinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1J3K

1j3k


Resolution: 2.38→54.66 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.905 / Occupancy max: 1 / Occupancy min: 1 / SU B: 9.275 / SU ML: 0.215 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.372 / ESU R Free: 0.283 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2864 3072 5.1 %RANDOM
Rwork0.2189 ---
obs0.2222 60475 99.08 %-
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: 48.8601 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1-2.54 Å20 Å20 Å2
2---1.18 Å20 Å2
3----1.36 Å2
Refinement stepCycle: LAST / Resolution: 2.38→54.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8867 0 168 438 9473
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0229268
X-RAY DIFFRACTIONr_angle_refined_deg1.4891.97312530
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.74751057
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.07424.732467
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.739151643
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6231538
X-RAY DIFFRACTIONr_chiral_restr0.0980.21339
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0216986
X-RAY DIFFRACTIONr_mcbond_it0.8631.55321
X-RAY DIFFRACTIONr_mcangle_it1.60128663
X-RAY DIFFRACTIONr_scbond_it1.83533947
X-RAY DIFFRACTIONr_scangle_it3.0014.53867
LS refinement shellResolution: 2.38→2.442 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 215 -
Rwork0.335 3852 -
all-4067 -
obs--91.11 %

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