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- PDB-4dp3: Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum di... -

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Basic information

Entry
Database: PDB / ID: 4dp3
TitleQuadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with P218 and NADPH
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / TRANSFERASE/INHIBITOR / Rossmann fold / Reductase / 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 / 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
Chem-MMV / Chem-NDP / PHOSPHATE ION / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.4 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 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.2Nov 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)146,2188
Polymers143,8162
Non-polymers2,4026
Water7,945441
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11110 Å2
ΔGint-51 kcal/mol
Surface area47880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.499, 156.198, 164.586
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: 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, V1/S / Plasmid: pET17b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: D9N170, dihydrofolate reductase, thymidylate synthase
#2: Chemical ChemComp-MMV / 3-(2-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid


Mass: 360.408 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H24N4O4
#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: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 441 / Source method: isolated from a natural source / Formula: H2O
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: 2.61 Å3/Da / Density % sol: 52.95 % / Mosaicity: 0.682 °
Crystal growTemperature: 297 K / Method: microbatch / pH: 4.5
Details: PEG 4000, 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: Nonius Kappa CCD / Detector: CCD / Date: Sep 1, 2008 / 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: 2.4→19.9 Å / Num. all: 57640 / Num. obs: 57735 / % possible obs: 96.5 % / Observed criterion σ(F): 1 / Biso Wilson estimate: 45.8 Å2 / Limit h max: 24 / Limit h min: 0 / Limit k max: 64 / Limit k min: 0 / Limit l max: 68 / Limit l min: 0 / Observed criterion F max: 2447998.49 / Observed criterion F min: 10.7 / Rmerge(I) obs: 0.047 / Χ2: 1.106 / Net I/σ(I): 21
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.4-2.490.24851071.546186.7
2.49-2.580.21653531.594190.8
2.58-2.70.17254931.613192.8
2.7-2.840.1356611.6195.8
2.84-3.020.10358411.5198.6
3.02-3.250.08359781.52199.7
3.25-3.580.05759201.294199.9
3.58-4.090.04660031.2199.9
4.09-5.140.03760620.8021100
5.14-200.03963170.657199.9

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
CNS1.3refinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
DENZOdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1J3K

1j3k


Resolution: 2.4→19.9 Å / Rfactor Rfree error: 0.004 / Occupancy max: 1 / Occupancy min: 1 / σ(F): 1
RfactorNum. reflection% reflection
Rfree0.239 2903 5 %
Rwork0.205 --
all-59702 -
obs-57640 96.5 %
Solvent computationSolvent model: CNS bulk solvent model used / Bsol: 45.8225 Å2 / ksol: 0.37 e/Å3
Displacement parametersBiso max: 124.14 Å2 / Biso mean: 49.2 Å2 / Biso min: 18.82 Å2
Baniso -1Baniso -2Baniso -3
1-13.88 Å20 Å20 Å2
2---3.28 Å20 Å2
3----10.6 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.34 Å0.28 Å
Luzzati d res low-5 Å
Luzzati sigma a0.35 Å0.3 Å
Luzzati d res high-2.4
Refinement stepCycle: LAST / Resolution: 2.4→19.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9068 0 158 441 9667
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_d1.34
X-RAY DIFFRACTIONc_mcbond_it1.5271.5
X-RAY DIFFRACTIONc_scbond_it1.8782
X-RAY DIFFRACTIONc_mcangle_it2.6652
X-RAY DIFFRACTIONc_scangle_it2.8242.5
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection RworkRfactor Rfree errorNum. reflection allNum. reflection obs% reflection obs (%)
2.4-2.510.3063094.80.27461660.0177347647588.1
2.51-2.640.3233495.20.26764120.0177408676191.3
2.64-2.810.2993124.50.24866630.0177371697594.6
2.81-3.020.2713815.20.23668770.0147389725898.2
3.02-3.330.2783865.20.22770090.0147422739599.6
3.33-3.810.2353895.20.270680.0127482745799.7
3.81-4.780.1923825.10.16471400.017532752299.9
4.78-19.90.213955.10.18674020.0117803779799.9
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1CNS_TOPPAR:protein_rep.param
X-RAY DIFFRACTION2CNS_TOPPAR:water_rep.param
X-RAY DIFFRACTION3ligands_1.par

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