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- PDB-4ky4: Crystal structure of non-classical TS inhibitor 2 in complex with... -

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Basic information

Entry
Database: PDB / ID: 4ky4
TitleCrystal structure of non-classical TS inhibitor 2 in complex with Toxoplasma gondii TS-DHFR
ComponentsBifunctional dihydrofolate reductase-thymidylate synthase
KeywordsOXIDOREDUCTASE / TRANSFERASE / synthase / bifunctional
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
Similarity search - Function
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 ...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. / Dihydrofolate reductase-like domain superfamily / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Aminopterin / Chem-1UE / Chem-NDP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Bifunctional dihydrofolate reductase-thymidylate synthase
Similarity search - Component
Biological speciesToxoplasma gondii (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.79 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 1.1Nov 15, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.2Sep 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)565,16040
Polymers550,7418
Non-polymers14,41932
Water0
1
A: Bifunctional dihydrofolate reductase-thymidylate synthase
B: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,29010
Polymers137,6852
Non-polymers3,6058
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6570 Å2
ΔGint-42 kcal/mol
Surface area41090 Å2
MethodPISA
2
C: Bifunctional dihydrofolate reductase-thymidylate synthase
D: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,29010
Polymers137,6852
Non-polymers3,6058
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6570 Å2
ΔGint-43 kcal/mol
Surface area41150 Å2
MethodPISA
3
E: Bifunctional dihydrofolate reductase-thymidylate synthase
F: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,29010
Polymers137,6852
Non-polymers3,6058
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6570 Å2
ΔGint-43 kcal/mol
Surface area41190 Å2
MethodPISA
4
G: Bifunctional dihydrofolate reductase-thymidylate synthase
H: Bifunctional dihydrofolate reductase-thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,29010
Polymers137,6852
Non-polymers3,6058
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6580 Å2
ΔGint-42 kcal/mol
Surface area41030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.539, 145.122, 176.159
Angle α, β, γ (deg.)89.970, 89.950, 89.890
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: 68842.656 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 / Deoxyuridine monophosphate


Mass: 308.182 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C9H13N2O8P
#3: Chemical
ChemComp-04J / Aminopterin / N-(4-{[(2,4-diaminopteridin-6-yl)methyl]amino}benzoyl)-L-glutamic acid / Aminopterin


Mass: 440.413 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C19H20N8O5 / Comment: chemotherapy, antineoplastic*YM
#4: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#5: Chemical
ChemComp-1UE / 2-amino-5-(phenylsulfanyl)-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one


Mass: 308.358 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C16H12N4OS

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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: 2.49 Å3/Da / Density % sol: 50.51 %
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
IDCrystal-ID
11
21
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1.1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Nov 4, 2012
Radiation
IDProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1SINGLE WAVELENGTHMx-ray1
2SINGLE WAVELENGTHMx-ray1
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.79→48.28 Å / Num. all: 128608 / Num. obs: 121332 / % possible obs: 94.34 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.7.0032refinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4EIL

4eil


Resolution: 2.79→48.28 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.905 / Occupancy max: 1 / Occupancy min: 0.42 / SU B: 16.948 / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R Free: 0.395
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2676 6475 5 %RANDOM
Rwork0.2198 ---
all0.2222 128608 --
obs0.2222 121332 97.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 202.23 Å2 / Biso mean: 79.025 Å2 / Biso min: 42.59 Å2
Baniso -1Baniso -2Baniso -3
1--1.1 Å20.25 Å2-0 Å2
2---3.58 Å2-0.25 Å2
3---4.67 Å2
Refinement stepCycle: LAST / Resolution: 2.79→48.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms31444 0 976 0 32420
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01933340
X-RAY DIFFRACTIONr_bond_other_d0.0030.0231368
X-RAY DIFFRACTIONr_angle_refined_deg1.6361.98845284
X-RAY DIFFRACTIONr_angle_other_deg0.9613.00871988
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0653880
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.73723.3161520
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.366155484
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.30115240
X-RAY DIFFRACTIONr_chiral_restr0.0890.24936
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02136864
X-RAY DIFFRACTIONr_gen_planes_other0.0010.027952
X-RAY DIFFRACTIONr_mcbond_it5.1647.41215688
X-RAY DIFFRACTIONr_mcbond_other5.1647.41115687
X-RAY DIFFRACTIONr_mcangle_it7.64111.09519512
LS refinement shellResolution: 2.793→2.866 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.362 437 -
Rwork0.342 7876 -
all-8313 -
obs--85.67 %

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