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- PDB-3um8: Wild-type Plasmodium falciparum DHFR-TS complexed with cycloguani... -

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Basic information

Entry
Database: PDB / ID: 3um8
TitleWild-type Plasmodium falciparum DHFR-TS complexed with cycloguanil and NADPH
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / TRANSFERASE/INHIBITOR / MALARIAL DHFR-TS / CYCLOGUANIL / ANTIFOLATE / NADPH / 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-1CY / Chem-NDP / PHOSPHATE ION / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.6 Å
AuthorsVanichtanankul, J. / Chitnumsub, P. / Kamchonwongpaisan, S. / 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 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)145,8408
Polymers143,6562
Non-polymers2,1846
Water8,215456
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10870 Å2
ΔGint-53 kcal/mol
Surface area47920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.761, 157.538, 164.509
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 / DHFR-TS


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 / Plasmid: pET17b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3)
References: UniProt: A7UD81, dihydrofolate reductase, thymidylate synthase
#2: Chemical ChemComp-1CY / 1-(4-chlorophenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine / Cycloguanil / Cycloguanil


Mass: 251.715 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H14ClN5 / Comment: inhibitor, antagonist*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-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.: 456 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE ENTIRE PROTEIN (REDUCTASE DOMAIN: RESIDUES 1-231; SYNTHASE DOMAIN: RESIDUES 283-608) WAS ...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: 2.65 Å3/Da / Density % sol: 53.59 % / Mosaicity: 0.365 °
Crystal growTemperature: 297 K / Method: microbatch / pH: 4.6
Details: 0.1mM sodium acetate, 25% (w/v) PEG 4000, 0.2M ammonium acetate, pH 4.6, microbatch, 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: Oct 30, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 47286 / % possible obs: 98.4 % / Rmerge(I) obs: 0.05 / Χ2: 1.089 / Net I/σ(I): 22.4
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.6-2.690.3144311.489193.2
2.69-2.80.25244861.52194.9
2.8-2.930.19846121.486197.6
2.93-3.080.14647001.461199.4
3.08-3.280.10647731.473199.9
3.28-3.530.07147301.413199.9
3.53-3.880.05248021.1871100
3.88-4.450.0448041.122199.8
4.45-5.60.03548790.8321100
5.6-500.03350690.355199.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
AMoREphasing
CNS1.2refinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→39.16 Å / Rfactor Rfree error: 0.005 / Occupancy max: 1 / Occupancy min: 1 / Data cutoff high absF: 220145 / 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
Rfree0.258 2367 5 %RANDOM
Rwork0.212 ---
obs-47165 98.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 48.0802 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso max: 90.7 Å2 / Biso mean: 52.5746 Å2 / Biso min: 16.6 Å2
Baniso -1Baniso -2Baniso -3
1-8.03 Å20 Å20 Å2
2--1.61 Å20 Å2
3----9.65 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.37 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.29 Å0.27 Å
Refinement stepCycle: LAST / Resolution: 2.6→39.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9044 0 140 456 9640
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d23.1
X-RAY DIFFRACTIONc_improper_angle_d0.82
X-RAY DIFFRACTIONc_mcbond_it1.341.5
X-RAY DIFFRACTIONc_mcangle_it2.322
X-RAY DIFFRACTIONc_scbond_it1.812
X-RAY DIFFRACTIONc_scangle_it2.72.5
LS refinement shellResolution: 2.6→2.69 Å / Rfactor Rfree error: 0.018 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.278 231 5.2 %
Rwork0.26 4207 -
all-4438 -
obs--93.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water.paramwater.top
X-RAY DIFFRACTION3ligands.paramligands.top
X-RAY DIFFRACTION4ion.paramion.top

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