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- PDB-4fgt: Allosteric peptidic inhibitor of human thymidylate synthase that ... -

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Basic information

Entry
Database: PDB / ID: 4fgt
TitleAllosteric peptidic inhibitor of human thymidylate synthase that stabilizes inactive conformation of the enzyme.
Components
  • CG peptide
  • Thymidylate synthase
Keywordstransferase/transferase inhibitor / dimer / mutant K47A of hTS / inactive hTS conformation / hTS complex with peptidic inhibitor / 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
Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Synthetic (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsTochowicz, A. / Finer-Moore, J. / Stroud, R.M. / Costi, M.P.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Alanine mutants of the interface residues of human thymidylate synthase decode key features of the binding mode of allosteric anticancer peptides.
Authors: Tochowicz, A. / Santucci, M. / Saxena, P. / Guaitoli, G. / Trande, M. / Finer-Moore, J. / Stroud, R.M. / Costi, M.P.
History
DepositionJun 4, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 4, 2015Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Thymidylate synthase
D: CG peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0765
Polymers37,7882
Non-polymers2883
Water1,65792
1
A: Thymidylate synthase
D: CG peptide
hetero molecules

A: Thymidylate synthase
D: CG peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,15310
Polymers75,5764
Non-polymers5766
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_555-x,-x+y,-z+1/31
Buried area7180 Å2
ΔGint-150 kcal/mol
Surface area22540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.807, 95.807, 83.285
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121
Components on special symmetry positions
IDModelComponents
11D-67-

GLN

21D-67-

GLN

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Components

#1: Protein Thymidylate synthase / / TS / TSase


Mass: 37262.586 Da / Num. of mol.: 1 / Mutation: K47A
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) / Strain (production host): BL21(DE3) / References: UniProt: P04818, thymidylate synthase
#2: Protein/peptide CG peptide


Mass: 525.618 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Synthetic (others)
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: 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: 57.88 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop / pH: 7.6
Details: 1.4M ammonium sulfate, 20 uM beta-ME and 0.1M Tris pH 7.6, VAPOR DIFFUSION, HANGING DROP, temperature 296K

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Data collection

DiffractionMean temperature: 273 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.115869 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 22, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.115869 Å / Relative weight: 1
ReflectionResolution: 2→40 Å / Num. obs: 29370 / % possible obs: 6.13 % / Redundancy: 6.1 %

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
DENZOdata reduction
SCALEPACKdata scaling
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→27.76 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.928 / Occupancy max: 1 / Occupancy min: 0.44 / SU B: 6.256 / SU ML: 0.081 / SU R Cruickshank DPI: 0.1399 / Cross valid method: THROUGHOUT / ESU R: 0.145 / ESU R Free: 0.136 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22906 1494 5.1 %RANDOM
Rwork0.19952 ---
obs0.20106 27803 97.31 %-
all-45158 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 51.105 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20.03 Å2-0 Å2
2--0.06 Å2-0 Å2
3----0.08 Å2
Refinement stepCycle: LAST / Resolution: 2→27.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2208 0 15 92 2315
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0280.0222288
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.1991.9733094
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6285272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.82123.482112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.15315397
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4961518
X-RAY DIFFRACTIONr_chiral_restr0.1890.2324
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.0211736
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.6941.51351
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.03722181
X-RAY DIFFRACTIONr_scbond_it4.1723937
X-RAY DIFFRACTIONr_scangle_it6.434.5911
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.003→2.054 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 123 -
Rwork0.239 2047 -
obs--99.95 %
Refinement TLS params.Method: refined / Origin x: 30.806 Å / Origin y: -36.751 Å / Origin z: 1.902 Å
111213212223313233
T0.1735 Å2-0.1431 Å20.0218 Å2-0.1921 Å2-0.0312 Å2--0.1442 Å2
L0.3052 °20.4803 °2-0.3002 °2-0.8073 °2-0.2889 °2--1.1435 °2
S-0.0486 Å °0.042 Å °-0.0081 Å °-0.1306 Å °0.1488 Å °-0.0409 Å °-0.0326 Å °0.1523 Å °-0.1002 Å °

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