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- PDB-6pf5: Crystal structure of human thymidylate synthase Delta (7-29) in c... -

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Basic information

Entry
Database: PDB / ID: 6pf5
TitleCrystal structure of human thymidylate synthase Delta (7-29) in complex with dUMP and 2-(2-(4-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)benzamido)-4-methoxyphenyl)acetic acid
ComponentsThymidylate synthase
Keywordstransferase/transferase inhibitor / Inhibitor / TS / TRANSFERASE / transferase-transferase inhibitor complex
Function / homology
Function and homology information


thymidylate synthase / Interconversion of nucleotide di- and triphosphates / sequence-specific mRNA binding / folic acid binding / thymidylate synthase activity / tetrahydrofolate interconversion / dTMP biosynthetic process / dTTP biosynthetic process / DNA biosynthetic process / G1/S-Specific Transcription ...thymidylate synthase / Interconversion of nucleotide di- and triphosphates / sequence-specific mRNA binding / folic acid binding / thymidylate synthase activity / tetrahydrofolate interconversion / dTMP biosynthetic process / dTTP biosynthetic process / DNA biosynthetic process / G1/S-Specific Transcription / mRNA regulatory element binding translation repressor activity / methylation / mitochondrial inner membrane / negative regulation of translation / mitochondrial matrix / mitochondrion / nucleus / cytoplasm / cytosol
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-OED / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.39 Å
AuthorsCzyzyk, D.J. / Valhondo, M. / Jorgensen, W.L. / Anderson, K.S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI083146 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)5T32AI007404 United States
CitationJournal: Eur.J.Med.Chem. / Year: 2019
Title: Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors.
Authors: Czyzyk, D.J. / Valhondo, M. / Deiana, L. / Tirado-Rives, J. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionJun 21, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,77912
Polymers132,7564
Non-polymers3,0238
Water2,198122
1
A: Thymidylate synthase
hetero molecules

D: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8896
Polymers66,3782
Non-polymers1,5114
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_445x-1/2,y-1/2,z1
Buried area5520 Å2
ΔGint-27 kcal/mol
Surface area20380 Å2
MethodPISA
2
B: Thymidylate synthase
hetero molecules

B: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8896
Polymers66,3782
Non-polymers1,5114
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,y,-z1
Buried area5480 Å2
ΔGint-27 kcal/mol
Surface area20400 Å2
MethodPISA
3
C: Thymidylate synthase
hetero molecules

C: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8896
Polymers66,3782
Non-polymers1,5114
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_456-x-1,y,-z+11
Buried area5510 Å2
ΔGint-29 kcal/mol
Surface area20350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.155, 85.134, 175.744
Angle α, β, γ (deg.)90.00, 89.93, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein
Thymidylate synthase / TSase


Mass: 33189.070 Da / Num. of mol.: 4
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 BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): TX-61 / References: UniProt: P04818, thymidylate synthase
#2: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP


Mass: 308.182 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H13N2O8P
#3: Chemical
ChemComp-OED / [2-({4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzene-1-carbonyl}amino)-4-methoxyphenyl]acetic acid


Mass: 447.443 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H21N5O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 122 / Source method: isolated from a natural source / Formula: H2O
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: 2.44 Å3/Da / Density % sol: 49.6 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, hanging drop / pH: 7
Details: Well solution 16 % PEG monomethyl ether 5000, 0.1 M Bis-Tris Drop ratio 1:1 enzyme mix/ well solution

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 12, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.39→50 Å / Num. obs: 49247 / % possible obs: 98.7 % / Redundancy: 3.6 % / CC1/2: 0.998 / Rsym value: 0.074 / Net I/σ(I): 13.25
Reflection shellResolution: 2.39→2.53 Å / Redundancy: 3.5 % / Mean I/σ(I) obs: 1.98 / Num. unique obs: 7465 / CC1/2: 0.78 / Rsym value: 0.777 / % possible all: 93.2

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Processing

Software
NameVersionClassification
PHENIX(1.15.2_3472: 000)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HZW

1hzw


Resolution: 2.39→42.577 Å / SU ML: 0.44 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 30.75
RfactorNum. reflection% reflection
Rfree0.2582 2011 4.09 %
Rwork0.2258 --
obs0.2271 49178 98.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.39→42.577 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8836 0 212 122 9170
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029292
X-RAY DIFFRACTIONf_angle_d0.57512659
X-RAY DIFFRACTIONf_dihedral_angle_d9.3875353
X-RAY DIFFRACTIONf_chiral_restr0.0411357
X-RAY DIFFRACTIONf_plane_restr0.0031634
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3903-2.45010.51251140.41182877X-RAY DIFFRACTION84
2.4501-2.51640.31211470.34383418X-RAY DIFFRACTION100
2.5164-2.59040.32211370.31363360X-RAY DIFFRACTION100
2.5904-2.6740.35241490.30313371X-RAY DIFFRACTION100
2.674-2.76950.33991460.28143379X-RAY DIFFRACTION100
2.7695-2.88040.29341430.26623442X-RAY DIFFRACTION100
2.8804-3.01150.3131470.28143407X-RAY DIFFRACTION100
3.0115-3.17020.33661450.24973391X-RAY DIFFRACTION100
3.1702-3.36870.23991470.23933382X-RAY DIFFRACTION100
3.3687-3.62870.24791460.23173377X-RAY DIFFRACTION100
3.6287-3.99360.23991470.22443424X-RAY DIFFRACTION100
3.9936-4.57090.23571500.1743393X-RAY DIFFRACTION99
4.5709-5.75670.22291480.19283444X-RAY DIFFRACTION100
5.7567-42.58420.20791450.18243502X-RAY DIFFRACTION99

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