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- PDB-6zxo: Crystal structure of His-tagged human thymidylate synthase (HT-hT... -

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Basic information

Entry
Database: PDB / ID: 6zxo
TitleCrystal structure of His-tagged human thymidylate synthase (HT-hTS) in complex with FdUMP and Raltitrexed (Tomudex)
Components(Thymidylate synthase) x 2
KeywordsTRANSFERASE / human Thymidylate Synthase / hTS / active conformation / FdUMP / Ratitrexed / Tomudex / Methyltransferase / folate pathway
Function / homology
Function and homology information


uracil metabolic process / response to organophosphorus / intestinal epithelial cell maturation / response to folic acid / Interconversion of nucleotide di- and triphosphates / response to vitamin A / thymidylate synthase / sequence-specific mRNA binding / cartilage development / tetrahydrofolate interconversion ...uracil metabolic process / response to organophosphorus / intestinal epithelial cell maturation / response to folic acid / Interconversion of nucleotide di- and triphosphates / response to vitamin A / thymidylate synthase / sequence-specific mRNA binding / cartilage development / tetrahydrofolate interconversion / thymidylate synthase activity / folic acid binding / dTMP biosynthetic process / dTTP biosynthetic process / DNA biosynthetic process / G1/S-Specific Transcription / developmental growth / dihydrofolate reductase activity / response to glucocorticoid / mRNA regulatory element binding translation repressor activity / response to progesterone / response to cytokine / liver regeneration / response to toxic substance / circadian rhythm / methylation / response to ethanol / mitochondrial inner membrane / negative regulation of translation / mitochondrial matrix / response to xenobiotic stimulus / protein homodimerization activity / mitochondrion / nucleus / cytosol / cytoplasm
Similarity search - Function
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
Similarity search - Domain/homology
TOMUDEX / 5-FLUORO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsPozzi, C. / Mangani, S.
Funding support Italy, 1items
OrganizationGrant numberCountry
Italian Association for Cancer ResearchIG10474 Italy
CitationJournal: Cancers (Basel) / Year: 2021
Title: Structural Bases for the Synergistic Inhibition of Human Thymidylate Synthase and Ovarian Cancer Cell Growth by Drug Combinations.
Authors: Pozzi, C. / Santucci, M. / Marverti, G. / D'Arca, D. / Tagliazucchi, L. / Ferrari, S. / Gozzi, G. / Losi, L. / Tassone, G. / Mangani, S. / Ponterini, G. / Costi, M.P.
History
DepositionJul 30, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: 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: Thymidylate synthase
B: Thymidylate synthase
C: Thymidylate synthase
D: Thymidylate synthase
E: Thymidylate synthase
F: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,98121
Polymers223,0876
Non-polymers4,89415
Water6,774376
1
A: Thymidylate synthase
B: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,0308
Polymers74,3372
Non-polymers1,6936
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8060 Å2
ΔGint-25 kcal/mol
Surface area21480 Å2
MethodPISA
2
C: Thymidylate synthase
D: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,9687
Polymers74,3372
Non-polymers1,6315
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7610 Å2
ΔGint-36 kcal/mol
Surface area21120 Å2
MethodPISA
3
E: Thymidylate synthase
F: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,9826
Polymers74,4132
Non-polymers1,5694
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7500 Å2
ΔGint-37 kcal/mol
Surface area21000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.720, 95.870, 103.840
Angle α, β, γ (deg.)112.390, 91.470, 109.170
Int Tables number1
Space group name H-MP1

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Components

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Protein , 2 types, 6 molecules ABCDEF

#1: Protein
Thymidylate synthase / / TSase


Mass: 37168.453 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYMS, TS, OK/SW-cl.29 / Plasmid: pQE80L / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P04818, thymidylate synthase
#2: Protein Thymidylate synthase / / TSase


Mass: 37244.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYMS, TS, OK/SW-cl.29 / Plasmid: pQE80L / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P04818, thymidylate synthase

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Non-polymers , 4 types, 391 molecules

#3: Chemical
ChemComp-D16 / TOMUDEX / ZD1694 / Raltitrexed / Raltitrexed


Mass: 458.488 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C21H22N4O6S / Feature type: SUBJECT OF INVESTIGATION / Comment: chemotherapy, inhibitor*YM
#4: Chemical
ChemComp-UFP / 5-FLUORO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE / Fluorodeoxyuridylate


Type: DNA linking / Mass: 326.172 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C9H12FN2O8P / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 376 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.41 Å3/Da / Density % sol: 48.98 %
Crystal growTemperature: 297 K / Method: vapor diffusion, hanging drop / pH: 9
Details: 25% (w/v) PEG4000, 30 mM ammonium sulfate and 20 mM beta-mercaptoethanol, 0.1 M TRIS pH 9

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 8, 2011
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.6→58.15 Å / Num. obs: 60436 / % possible obs: 96 % / Observed criterion σ(I): 2 / Redundancy: 1.9 % / Biso Wilson estimate: 48.2 Å2 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.077 / Rrim(I) all: 0.11 / Net I/σ(I): 6.5
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.367 / Mean I/σ(I) obs: 2 / Num. unique obs: 8757 / Rrim(I) all: 0.518 / Rsym value: 0.367 / % possible all: 95.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HVY

1hvy


Resolution: 2.6→47.33 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.932 / SU B: 12.341 / SU ML: 0.246 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.255 / ESU R Free: 0.311 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2317 3084 5.1 %RANDOM
Rwork0.1716 ---
obs0.1746 57340 95.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 99.9 Å2 / Biso mean: 51.581 Å2 / Biso min: 22.38 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å20.01 Å2-0.01 Å2
2---0 Å20.03 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.306 Å
Refinement stepCycle: final / Resolution: 2.6→47.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13609 0 330 376 14315
Biso mean--52.86 49.49 -
Num. residues----1727
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01214312
X-RAY DIFFRACTIONr_angle_refined_deg1.6111.67119427
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.51551720
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.82221.44736
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.558152262
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0741599
X-RAY DIFFRACTIONr_chiral_restr0.1160.21797
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211094
LS refinement shellResolution: 2.6→2.667 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.333 222 -
Rwork0.322 4227 -
all-4449 -
obs--95.7 %

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