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- PDB-4kya: Crystal structure of non-classical TS inhibitor 3 in complex with... -

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Basic information

Entry
Database: PDB / ID: 4kya
TitleCrystal structure of non-classical TS inhibitor 3 in complex with Toxoplasma gondii TS-DHFR
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / TRANSFERASE/INHIBITOR / synthase / bifunctional / chimera protein / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


thymidylate synthase / thymidylate synthase activity / dTMP biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / methylation / mitochondrion / cytosol
Similarity search - Function
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 ...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 domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-1UG / FOLIC ACID / Chem-NDP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesToxoplasma gondii (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.263 Å
AuthorsSharma, H. / Anderson, K.S.
CitationJournal: ACS Med Chem Lett / Year: 2013
Title: Discovery of potent and selective inhibitors of Toxoplasma gondii thymidylate synthase for opportunistic infections.
Authors: Zaware, N. / Sharma, H. / Yang, J. / Devambatla, R.K. / Queener, S.F. / Anderson, K.S. / Gangjee, A.
History
DepositionMay 28, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 6, 2014Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2017Group: Data collection / Refinement description / Source and taxonomy
Category: diffrn_detector / entity_src_gen / software / Item: _diffrn_detector.detector
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.location / _software.name / _software.type / _software.version
Revision 1.4Sep 20, 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
C: Bifunctional dihydrofolate reductase-thymidylate synthase
D: Bifunctional dihydrofolate reductase-thymidylate synthase
E: Bifunctional dihydrofolate reductase-thymidylate synthase
F: Bifunctional dihydrofolate reductase-thymidylate synthase
G: Bifunctional dihydrofolate reductase-thymidylate synthase
H: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)528,54240
Polymers513,7148
Non-polymers14,82732
Water00
1
A: Bifunctional dihydrofolate reductase-thymidylate synthase
B: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,13510
Polymers128,4292
Non-polymers3,7078
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6670 Å2
ΔGint-41 kcal/mol
Surface area41200 Å2
MethodPISA
2
C: Bifunctional dihydrofolate reductase-thymidylate synthase
D: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,13510
Polymers128,4292
Non-polymers3,7078
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6660 Å2
ΔGint-41 kcal/mol
Surface area41270 Å2
MethodPISA
3
E: Bifunctional dihydrofolate reductase-thymidylate synthase
F: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,13510
Polymers128,4292
Non-polymers3,7078
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6680 Å2
ΔGint-41 kcal/mol
Surface area41170 Å2
MethodPISA
4
G: Bifunctional dihydrofolate reductase-thymidylate synthase
H: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,13510
Polymers128,4292
Non-polymers3,7078
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6640 Å2
ΔGint-42 kcal/mol
Surface area41200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.531, 145.079, 176.614
Angle α, β, γ (deg.)90.07, 89.96, 90.07
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Bifunctional dihydrofolate reductase-thymidylate synthase / DHFR-TS / Dihydrofolate reductase / Thymidylate synthase


Mass: 64214.312 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Production host: Escherichia coli (E. coli)
References: UniProt: Q07422, dihydrofolate reductase, thymidylate synthase
#2: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C9H13N2O8P
#3: Chemical
ChemComp-1UG / 2-Amino-5-(1-naphthylsulfanyl)-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one


Mass: 358.416 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C20H14N4OS
#4: Chemical
ChemComp-FOL / FOLIC ACID


Mass: 441.397 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C19H19N7O6
#5: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H30N7O17P3

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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: 2.67 Å3/Da / Density % sol: 53.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 18% Peg 3350, 0.1 M Potassium Formate, pH 7.3, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21
Diffraction source
SourceSiteBeamlineIDWavelength (Å)
SYNCHROTRONNSLS X2511.1
2
Detector
TypeIDDetectorDate
PSI PILATUS 6M1PIXELApr 13, 2013
2
Radiation
IDMonochromatorProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1Si 111SINGLE WAVELENGTHMx-ray1
2SINGLE WAVELENGTHMx-ray1
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 3.263→46.657 Å / Num. obs: 81521 / % possible obs: 95 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 3.263→3.348 Å / % possible all: 92.95

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHENIX1.9_1692refinement
SCALEPACKdata scaling
PHASERphasing
REFMAC5.7.0029refinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4EIL

4eil


Resolution: 3.263→46.657 Å / Cor.coef. Fo:Fc: 0.901 / Cor.coef. Fo:Fc free: 0.833 / Occupancy max: 1 / Occupancy min: 0 / SU ML: 0.39 / σ(F): 1.99 / Phase error: 23.56 / Stereochemistry target values: ML
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflection
Rfree0.241 4069 5 %
Rwork0.1825 --
obs0.1854 81456 98.55 %
all-81521 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.667 Å2
Baniso -1Baniso -2Baniso -3
1--0.47 Å2-0.17 Å20 Å2
2---2.3 Å20.13 Å2
3---2.77 Å2
Refinement stepCycle: LAST / Resolution: 3.263→46.657 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms32064 0 1008 0 33072
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00334064
X-RAY DIFFRACTIONf_angle_d0.76546292
X-RAY DIFFRACTIONf_dihedral_angle_d15.46712288
X-RAY DIFFRACTIONf_chiral_restr0.0294996
X-RAY DIFFRACTIONf_plane_restr0.0045856
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.2634-3.30180.30931340.2272386X-RAY DIFFRACTION88
3.3018-3.3420.33421380.24452686X-RAY DIFFRACTION98
3.342-3.38430.31551360.23772596X-RAY DIFFRACTION98
3.3843-3.42880.28531340.24192620X-RAY DIFFRACTION98
3.4288-3.47580.33361310.22442669X-RAY DIFFRACTION98
3.4758-3.52540.28441530.20642709X-RAY DIFFRACTION99
3.5254-3.5780.26061240.20872691X-RAY DIFFRACTION99
3.578-3.63390.24351540.19022638X-RAY DIFFRACTION99
3.6339-3.69350.24851270.19712685X-RAY DIFFRACTION99
3.6935-3.75720.26331520.19422715X-RAY DIFFRACTION99
3.7572-3.82540.26331360.18682745X-RAY DIFFRACTION99
3.8254-3.8990.26091430.18342552X-RAY DIFFRACTION99
3.899-3.97850.23381450.17752669X-RAY DIFFRACTION99
3.9785-4.0650.20111080.17332768X-RAY DIFFRACTION99
4.065-4.15950.23941650.16152646X-RAY DIFFRACTION99
4.1595-4.26340.21611380.15162657X-RAY DIFFRACTION99
4.2634-4.37860.20261500.16112679X-RAY DIFFRACTION99
4.3786-4.50740.21221470.14382745X-RAY DIFFRACTION99
4.5074-4.65270.18871430.14032595X-RAY DIFFRACTION99
4.6527-4.81890.21321560.16452769X-RAY DIFFRACTION99
4.8189-5.01160.20761610.16432609X-RAY DIFFRACTION99
5.0116-5.23940.26271310.16512670X-RAY DIFFRACTION99
5.2394-5.51520.25271430.18212705X-RAY DIFFRACTION99
5.5152-5.86010.19841180.17912749X-RAY DIFFRACTION100
5.8601-6.31160.23121520.19042654X-RAY DIFFRACTION100
6.3116-6.94490.22731550.18492698X-RAY DIFFRACTION100
6.9449-7.94560.26581280.17822706X-RAY DIFFRACTION100
7.9456-9.99440.19291360.16092693X-RAY DIFFRACTION100
9.9944-46.66190.24641310.20632683X-RAY DIFFRACTION98

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