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- PDB-6a2p: Crystal structure of quadruple mutant (N51I+C59R+S108N+I164L) Pla... -

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Basic information

Entry
Database: PDB / ID: 6a2p
TitleCrystal structure of quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum DHFR-TS complexed with BT3, NADPH, and dUMP
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Rossmann fold / Dual-binding Inhibitor / OXIDOREDUCTASE-OXIDOREDUCTASE 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, 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-9RR / 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: 2.6 Å
Model detailsCrystal structure of quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum DHFR-TS ...Crystal structure of quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum DHFR-TS complexed with BT3, 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)146,1777
Polymers143,8162
Non-polymers2,3615
Water3,567198
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10670 Å2
ΔGint-44 kcal/mol
Surface area48820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.243, 158.900, 167.600
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)
Gene: DHFR-TS, V1/S / Plasmid: pET17b / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: D9N170
#2: Chemical ChemComp-9RR / 5,5'-[propane-1,3-diylbis(oxy-4,1-phenylene)]bis(6-ethylpyrimidine-2,4-diamine)


Mass: 500.595 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H32N8O2
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 1 / 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.: 198 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsThe quadruple mutations (N51I, C59R, S108N, I164L) of DHFR-TS is found in plasmodium falciparum ...The quadruple mutations (N51I, C59R, S108N, I164L) of DHFR-TS is found in plasmodium falciparum (ORF Name V1/S).

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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: 2.74 Å3/Da / Density % sol: 55.15 % / Mosaicity: 0.001 °
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, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→30 Å / Num. obs: 46152 / % possible obs: 93.8 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.078 / Χ2: 1.434 / Net I/σ(I): 17.6 / Num. measured all: 153889
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.6-2.693.10.39645341.285193.1
2.69-2.83.10.30745161.384194
2.8-2.933.10.23745351.5193.5
2.93-3.083.10.18645131.654192.6
3.08-3.2830.13445091.769192.7
3.28-3.5330.10145491.747193.3
3.53-3.883.10.08746381.647194.5
3.88-4.443.50.07546871.541195.1
4.44-5.593.90.07247511.362195
5.59-304.20.0549200.863194.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
HKL-2000data scaling
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1J3K

1j3k


Resolution: 2.6→25.28 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.904 / SU B: 10.985 / SU ML: 0.237 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.716 / ESU R Free: 0.337 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2671 2304 5 %RANDOM
Rwork0.2063 ---
obs0.2094 43761 92.82 %-
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: 62.893 Å2 / Biso min: 23.11 Å2
Baniso -1Baniso -2Baniso -3
1-4.87 Å20 Å2-0 Å2
2---2.69 Å20 Å2
3----2.18 Å2
Refinement stepCycle: final / Resolution: 2.6→25.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9132 0 162 198 9492
Biso mean--64.08 53.63 -
Num. residues----1098
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0149517
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178516
X-RAY DIFFRACTIONr_angle_refined_deg1.9081.75312863
X-RAY DIFFRACTIONr_angle_other_deg0.651.71619948
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.52951092
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.07921.68387
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.952151520
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3481538
X-RAY DIFFRACTIONr_chiral_restr0.0860.21206
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0210459
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021890
LS refinement shellResolution: 2.6→2.667 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 155 -
Rwork0.287 2748 -
all-2903 -
obs--81.43 %

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