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- PDB-5hs3: Human thymidylate synthase complexed with dUMP and 3-amino-2-benz... -

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Basic information

Entry
Database: PDB / ID: 5hs3
TitleHuman thymidylate synthase complexed with dUMP and 3-amino-2-benzoyl-4-methylthieno[2,3-b]pyridin-6-ol
ComponentsThymidylate synthase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / nhibitor / 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 / thymidylate synthase / response to vitamin A / 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 / thymidylate synthase / response to vitamin A / sequence-specific mRNA binding / cartilage development / tetrahydrofolate interconversion / folic acid binding / thymidylate synthase activity / dTMP biosynthetic process / dTTP biosynthetic process / DNA biosynthetic process / G1/S-Specific Transcription / developmental growth / response to glucocorticoid / mRNA regulatory element binding translation repressor activity / response to cytokine / response to progesterone / liver regeneration / response to toxic substance / circadian rhythm / response to ethanol / methylation / 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, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-KI3 / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.103 Å
AuthorsChen, D. / Almqvist, H. / Axelsson, H. / Jafari, R. / Mateus, A. / Haraldsson, M. / Larsson, A. / Artursson, P. / Molina, D.M. / Lundback, T. / Nordlund, P.
Funding support Singapore, 1items
OrganizationGrant numberCountry
Nanyang Technological UniversityM060080004.70301200 Singapore
CitationJournal: Nat Commun / Year: 2016
Title: CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
Authors: Almqvist, H. / Axelsson, H. / Jafari, R. / Chen, D. / Mateus, A. / Haraldsson, M. / Larsson, A. / Molina, D.M. / Artursson, P. / Lundback, T. / Nordlund, P.
History
DepositionJan 25, 2016Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Feb 24, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 30, 2016Group: Database references
Revision 1.2Apr 6, 2016Group: Database references
Revision 1.3Feb 19, 2020Group: Data collection / Derived calculations / Category: diffrn_source / pdbx_struct_oper_list
Item: _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Nov 8, 2023Group: 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

Downloads & links

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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)201,70415
Polymers199,0026
Non-polymers2,7029
Water19811
1
A: Thymidylate synthase
D: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,2355
Polymers66,3342
Non-polymers9013
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Thymidylate synthase
F: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,2355
Polymers66,3342
Non-polymers9013
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Thymidylate synthase
E: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,2355
Polymers66,3342
Non-polymers9013
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)108.202, 108.202, 313.931
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein
Thymidylate synthase / TSase


Mass: 33167.047 Da / Num. of mol.: 6 / Fragment: UNP residues 26-313
Source method: isolated from a genetically manipulated source
Details: Residue 1-25 deleted / Source: (gene. exp.) Homo sapiens (human) / Gene: TYMS, TS / Production host: Escherichia coli (E. coli) / References: UniProt: P04818, thymidylate synthase
#2: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Formula: C9H13N2O8P
#3: Chemical ChemComp-KI3 / 3-amino-2-benzoyl-4-methylthieno[2,3-b]pyridin-6-ol


Mass: 284.333 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C15H12N2O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 11 / 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: 2.32 Å3/Da / Density % sol: 46.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M sodium cacodylate, 15% PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Sep 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 3.1→30 Å / Num. obs: 34749 / % possible obs: 99.9 % / Redundancy: 11.9 % / Net I/σ(I): 15.56

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HVY

1hvy


Resolution: 3.103→28.106 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2684 1664 4.83 %
Rwork0.1798 --
obs0.1843 34453 99.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.103→28.106 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13594 0 180 11 13785
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01414149
X-RAY DIFFRACTIONf_angle_d1.09619201
X-RAY DIFFRACTIONf_dihedral_angle_d20.3715303
X-RAY DIFFRACTIONf_chiral_restr0.062024
X-RAY DIFFRACTIONf_plane_restr0.0052483
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1029-3.19410.3791610.24312648X-RAY DIFFRACTION99
3.1941-3.2970.30131380.22342689X-RAY DIFFRACTION100
3.297-3.41470.32951240.23252690X-RAY DIFFRACTION100
3.4147-3.55120.31661260.2152707X-RAY DIFFRACTION100
3.5512-3.71240.25421360.19332723X-RAY DIFFRACTION100
3.7124-3.90770.30381280.18332702X-RAY DIFFRACTION100
3.9077-4.15180.25281220.17462744X-RAY DIFFRACTION100
4.1518-4.47120.2271470.15562719X-RAY DIFFRACTION100
4.4712-4.9190.21661430.14832741X-RAY DIFFRACTION99
4.919-5.62580.28041130.17652780X-RAY DIFFRACTION99
5.6258-7.06920.29141700.19022757X-RAY DIFFRACTION99
7.0692-28.1070.24081560.15052889X-RAY DIFFRACTION97

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