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- PDB-4e28: Structure of human thymidylate synthase in inactive conformation ... -

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Basic information

Entry
Database: PDB / ID: 4.0E+28
TitleStructure of human thymidylate synthase in inactive conformation with a novel non-peptidic inhibitor
ComponentsThymidylate synthase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Human Thymidylate Synthase (hTS) inactive conformation / hTS-Inhibitor complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
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; 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-0MZ / Chem-9MZ / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.302 Å
AuthorsTochowicz, A. / Finer-Moore, J. / Stroud, R.M. / Costi, M.P.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Inhibitor of ovarian cancer cells growth by virtual screening: a new thiazole derivative targeting human thymidylate synthase.
Authors: Carosati, E. / Tochowicz, A. / Marverti, G. / Guaitoli, G. / Benedetti, P. / Ferrari, S. / Stroud, R.M. / Finer-Moore, J. / Luciani, R. / Farina, D. / Cruciani, G. / Costi, M.P.
History
DepositionMar 7, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 14, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 12, 2012Group: Database references
Revision 1.2Nov 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 1.3Sep 13, 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_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _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

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Assembly

Deposited unit
A: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3865
Polymers37,3211
Non-polymers1,0654
Water1,65792
1
A: Thymidylate synthase
hetero molecules

A: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,77110
Polymers74,6412
Non-polymers2,1308
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555x-y,-y,-z+2/31
Buried area5110 Å2
ΔGint-80 kcal/mol
Surface area21300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.747, 95.747, 82.407
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein Thymidylate synthase / / TS / TSase


Mass: 37320.688 Da / Num. of mol.: 1 / Fragment: UNP residues 26-311
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYMS, TS, OK/SW-cl.29 / Production host: Escherichia coli (E. coli) / References: UniProt: P04818, thymidylate synthase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-0MZ / 2-{(2Z,5S)-4-hydroxy-2-[(2E)-(2-hydroxybenzylidene)hydrazinylidene]-2,5-dihydro-1,3-thiazol-5-yl}-N-[3-(trifluoromethyl)phenyl]acetamide


Mass: 436.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15F3N4O3S
#4: Chemical ChemComp-9MZ / 2-{(5S)-2-[(2E)-2-(2-hydroxybenzylidene)hydrazinyl]-4-oxo-4,5-dihydro-1,3-thiazol-5-yl}-N-[3-(trifluoromethyl)phenyl]acetamide


Mass: 436.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15F3N4O3S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 92 / Source method: isolated from a natural source / Formula: H2O

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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: 2.92 Å3/Da / Density % sol: 57.9 %
Crystal growTemperature: 273 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1.4 M ammonium sulfate, 20 uM BME, 0.1 M Tris, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 273K

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Data collection

DiffractionMean temperature: 273 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11588 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 20, 2009
RadiationMonochromator: KHOZU double flat crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11588 Å / Relative weight: 1
ReflectionResolution: 2.3→40 Å / Num. all: 19711 / Num. obs: 18949 / % possible obs: 96.1 % / Redundancy: 3.2 % / Rmerge(I) obs: 0.061 / Rsym value: 0.102 / Net I/σ(I): 11

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIX1.7.2_869refinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1HVY

1hvy


Resolution: 2.302→29.225 Å / Occupancy max: 1 / Occupancy min: 0 / SU ML: 0.59 / σ(F): 1.34 / Phase error: 18.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2289 973 5.14 %
Rwork0.1882 --
obs0.1903 18948 96.14 %
Solvent computationShrinkage radii: 0.98 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 67.929 Å2 / ksol: 0.4 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.145 Å20 Å20 Å2
2---0.145 Å2-0 Å2
3---0.29 Å2
Refinement stepCycle: LAST / Resolution: 2.302→29.225 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2042 0 70 92 2204
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092167
X-RAY DIFFRACTIONf_angle_d1.2462932
X-RAY DIFFRACTIONf_dihedral_angle_d18.52813
X-RAY DIFFRACTIONf_chiral_restr0.079305
X-RAY DIFFRACTIONf_plane_restr0.005373
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3022-2.42350.30321480.22882601X-RAY DIFFRACTION100
2.4235-2.57530.20451410.18042650X-RAY DIFFRACTION100
2.5753-2.77390.25421340.17412627X-RAY DIFFRACTION100
2.7739-3.05280.23561410.18182651X-RAY DIFFRACTION100
3.0528-3.4940.23411450.1832635X-RAY DIFFRACTION99
3.494-4.39960.2121420.17842445X-RAY DIFFRACTION91
4.3996-29.22780.22581220.2022366X-RAY DIFFRACTION84
Refinement TLS params.Method: refined / Origin x: 50.4411 Å / Origin y: -8.132 Å / Origin z: 16.1033 Å
111213212223313233
T0.3214 Å20.0484 Å2-0.0448 Å2-0.1741 Å2-0.0227 Å2--0.2558 Å2
L1.0134 °2-0.6846 °20.2006 °2-1.9885 °20.4414 °2--1.4625 °2
S0.2217 Å °0.1197 Å °-0.2244 Å °-0.2258 Å °-0.095 Å °0.1052 Å °0.074 Å °-0.0802 Å °0.0017 Å °
Refinement TLS groupSelection details: all

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