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- PDB-3n5e: Crystal Structure of human thymidylate synthase bound to a peptid... -

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Basic information

Entry
Database: PDB / ID: 3n5e
TitleCrystal Structure of human thymidylate synthase bound to a peptide inhibitor
Components
  • (Thymidylate synthase) x 2
  • Synthetic peptide LR
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / peptide inhibitor / protein-peptide complex / interface inhibitor / TRANSFERASE / 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
Synthetic peptide LR / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsPozzi, C. / Cardinale, D. / Guaitoli, G. / Tondi, D. / Luciani, R. / Myllykallio, H. / Ferrari, S. / Costi, M.P. / Mangani, S.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2011
Title: Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase.
Authors: Cardinale, D. / Guaitoli, G. / Tondi, D. / Luciani, R. / Henrich, S. / Salo-Ahen, O.M. / Ferrari, S. / Marverti, G. / Guerrieri, D. / Ligabue, A. / Frassineti, C. / Pozzi, C. / Mangani, S. / ...Authors: Cardinale, D. / Guaitoli, G. / Tondi, D. / Luciani, R. / Henrich, S. / Salo-Ahen, O.M. / Ferrari, S. / Marverti, G. / Guerrieri, D. / Ligabue, A. / Frassineti, C. / Pozzi, C. / Mangani, S. / Fessas, D. / Guerrini, R. / Ponterini, G. / Wade, R.C. / Costi, M.P.
History
DepositionMay 25, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 8, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 24, 2013Group: Database references
Revision 1.3Sep 6, 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
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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Thymidylate synthase
B: Thymidylate synthase
D: Synthetic peptide LR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,9637
Polymers75,5793
Non-polymers3844
Water4,594255
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6690 Å2
ΔGint-92 kcal/mol
Surface area22530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.109, 96.109, 82.240
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31

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Components

#1: Protein Thymidylate synthase / / TSase / TS


Mass: 37306.730 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 / Production host: Escherichia coli (E. coli) / References: UniProt: P04818, thymidylate synthase
#2: Protein Thymidylate synthase / / TSase / TS


Mass: 37260.637 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 / Production host: Escherichia coli (E. coli) / References: UniProt: P04818, thymidylate synthase
#3: Protein/peptide Synthetic peptide LR


Type: PolypeptidePeptide / Class: Inhibitor / Mass: 1011.177 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: Synthetic Peptide (8mer) / References: Synthetic peptide LR
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 255 / 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: 2.9 Å3/Da / Density % sol: 57.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.3
Details: 25% saturated Ammonium Sulfate, 20mM BME, 0.1M TRIS pH8.3, VAPOR DIFFUSION, SITTING DROP, temperature 293.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.947 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 17, 2008
RadiationMonochromator: Silicon (1 1 1) channel-cut / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.947 Å / Relative weight: 1
ReflectionResolution: 2.26→83.33 Å / Num. obs: 39745 / % possible obs: 99.8 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 2 / Redundancy: 11 % / Biso Wilson estimate: 45.2 Å2 / Rmerge(I) obs: 0.071 / Rsym value: 0.071 / Net I/σ(I): 25.9
Reflection shellResolution: 2.26→2.38 Å / Redundancy: 11.2 % / Rmerge(I) obs: 0.303 / Mean I/σ(I) obs: 6.7 / Num. unique all: 5857 / Rsym value: 0.303 / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
MOLREPphasing
REFMAC5.5.0102refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1YPV

1ypv


Resolution: 2.26→83.23 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.943 / SU B: 10.146 / SU ML: 0.116 / Cross valid method: THROUGHOUT / σ(F): 1 / σ(I): 2 / ESU R: 0.212 / ESU R Free: 0.178 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.22136 1990 5 %RANDOM
Rwork0.18768 ---
all0.2047 39745 --
obs0.18939 37678 99.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.258 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyze
FreeObs
Luzzati sigma a0.178 Å0.212 Å
Refinement stepCycle: LAST / Resolution: 2.26→83.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4339 0 20 255 4614
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0224466
X-RAY DIFFRACTIONr_angle_refined_deg1.4961.9746035
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8215529
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.81623.318214
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.66915773
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6941535
X-RAY DIFFRACTIONr_chiral_restr0.110.2636
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213383
X-RAY DIFFRACTIONr_mcbond_it0.8021.52657
X-RAY DIFFRACTIONr_mcangle_it1.56524293
X-RAY DIFFRACTIONr_scbond_it2.31531809
X-RAY DIFFRACTIONr_scangle_it3.744.51742
LS refinement shellResolution: 2.26→2.319 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.388 141 -
Rwork0.308 2773 -
obs-2773 98.75 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.8053-0.5876-0.18822.446-0.26392.02670.27290.27440.291-0.3266-0.0901-0.1716-0.1080.1088-0.18280.20770.04650.07470.05440.04750.1614-49.49787.86350.2202
21.76760.58930.23762.5073-0.16911.97880.2715-0.2507-0.2930.3391-0.0738-0.18140.10960.1101-0.19780.2122-0.047-0.07930.05190.0470.1485-49.4603-7.913123.5995
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-10 - 9999
2X-RAY DIFFRACTION2B-10 - 9999

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