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- PDB-3um5: Double mutant (A16V+S108T) Plasmodium falciparum dihydrofolate re... -

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Basic information

Entry
Database: PDB / ID: 3um5
TitleDouble mutant (A16V+S108T) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS-T9/94) complexed with pyrimethamine, NADPH, and dUMP
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / TRANSFERASE/INHIBITOR / MALARIAL DHFR-TS / PYRIMETHAMINE / ANTIFOLATE / NAPDH / DUMP / TRANSFERASE-INHIBITOR COMPLEX
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/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
Chem-CP6 / Chem-NDP / 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: 2.4 Å
AuthorsVanichtanankul, J. / Kamchonwongpaisan, S. / Chitnumsub, P. / Yuthavong, Y.
CitationJournal: Antimicrob.Agents Chemother. / Year: 2012
Title: Combined Spatial Limitation around Residues 16 and 108 of Plasmodium falciparum Dihydrofolate Reductase Explains Resistance to Cycloguanil.
Authors: Vanichtanankul, J. / Taweechai, S. / Uttamapinant, C. / Chitnumsub, P. / Vilaivan, T. / Yuthavong, Y. / Kamchonwongpaisan, S.
History
DepositionNov 12, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jul 18, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 1, 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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

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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)146,3458
Polymers143,7402
Non-polymers2,6056
Water14,070781
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13280 Å2
ΔGint-56 kcal/mol
Surface area46640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.529, 155.119, 165.257
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: 71870.078 Da / Num. of mol.: 2 / Mutation: A16V, S108T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: dhfr-ts / Plasmid: pET17b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3)
References: UniProt: A7UD81, dihydrofolate reductase, thymidylate synthase
#2: Chemical ChemComp-CP6 / 5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE / PYRIMETHAMINE / Pyrimethamine


Mass: 248.711 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H13ClN4 / Comment: medication, antiparasitic*YM
#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-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP / Deoxyuridine monophosphate


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


Mass: 18.015 Da / Num. of mol.: 781 / Source method: isolated from a natural source / Formula: H2O
Sequence details1. THE DOUBLE MUTATIONS (A16V, S108T) OF DHFR-TS IS FOUND IN PLASMODIUM FALCIPARUM STRAIN T9/94. 2. ...1. THE DOUBLE MUTATIONS (A16V, S108T) OF DHFR-TS IS FOUND IN PLASMODIUM FALCIPARUM STRAIN T9/94. 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: 2.52 Å3/Da / Density % sol: 51.2 %
Crystal growTemperature: 297 K / Method: evaporation / pH: 4.6
Details: 0.1mM SODIUM ACETATE, 25% (W/V) PEG 4000, 0.2M AMMONIUM ACETATE, PH 4.6, EVAPORATION, temperature 297K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418 Å
DetectorType: Nonius Kappa CCD / Detector: CCD / Date: Sep 20, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. obs: 57153 / Biso Wilson estimate: 35.7 Å2

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Processing

Software
NameVersionClassification
HKL-2000data collection
AMoREphasing
CNS1.2refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1j3i

1j3i


Resolution: 2.4→28.28 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 246494.66 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.254 2885 5.1 %RANDOM
Rwork0.202 ---
obs0.202 57048 98.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 54.754 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso mean: 46.9 Å2
Baniso -1Baniso -2Baniso -3
1-9.24 Å20 Å20 Å2
2---0.07 Å20 Å2
3----9.17 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.36 Å0.28 Å
Luzzati d res low-5 Å
Luzzati sigma a0.42 Å0.32 Å
Refinement stepCycle: LAST / Resolution: 2.4→28.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9056 0 170 781 10007
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.72
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.411.5
X-RAY DIFFRACTIONc_mcangle_it2.432
X-RAY DIFFRACTIONc_scbond_it1.872
X-RAY DIFFRACTIONc_scangle_it2.772.5
LS refinement shellResolution: 2.4→2.49 Å / Rfactor Rfree error: 0.02 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.342 282 5.2 %
Rwork0.302 5137 -
obs--94.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water.paramligands.top
X-RAY DIFFRACTION3ligands.paramwater.top

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