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- PDB-6pf4: Crystal structure of human thymidylate synthase Delta (7-29) in c... -

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Basic information

Entry
Database: PDB / ID: 6pf4
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)phenyl)acetic acid
ComponentsThymidylate synthase
Keywordstransferase/transferase inhibitor / inhibitor / TS / 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 / 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 / thymidylate synthase activity / folic acid binding / 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-OF7 / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.854 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
B: Thymidylate synthase
A: Thymidylate synthase
C: Thymidylate synthase
D: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,65912
Polymers132,7564
Non-polymers2,9028
Water46826
1
B: Thymidylate synthase
D: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8296
Polymers66,3782
Non-polymers1,4514
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5580 Å2
ΔGint-23 kcal/mol
Surface area20520 Å2
MethodPISA
2
A: Thymidylate synthase
hetero molecules

C: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8296
Polymers66,3782
Non-polymers1,4514
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_544-x+1/2,-y-1,z-1/21
Buried area5640 Å2
ΔGint-23 kcal/mol
Surface area20270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.190, 96.437, 135.719
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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-OF7 / [2-({4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzene-1-carbonyl}amino)phenyl]acetic acid


Mass: 417.417 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H19N5O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 26 / 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: 2.31 Å3/Da / Density % sol: 46.8 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Well solution 28 % PEG 4000, 0.2 M lithium sulfate, 0.1 M 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: 0.97915 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 9, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.84→50 Å / Num. obs: 28415 / % possible obs: 97.6 % / Redundancy: 7 % / CC1/2: 0.995 / Rsym value: 0.176 / Net I/σ(I): 10.29
Reflection shellResolution: 2.84→3.02 Å / Redundancy: 6 % / Mean I/σ(I) obs: 3.2 / Num. unique obs: 3981 / CC1/2: 0.928 / Rsym value: 0.737 / % possible all: 86

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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: 2.854→47.547 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.52
RfactorNum. reflection% reflection
Rfree0.2537 1414 5.01 %
Rwork0.2387 --
obs0.2395 28239 98.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.854→47.547 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8968 0 204 26 9198
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0039416
X-RAY DIFFRACTIONf_angle_d0.61512795
X-RAY DIFFRACTIONf_dihedral_angle_d10.2045469
X-RAY DIFFRACTIONf_chiral_restr0.0431356
X-RAY DIFFRACTIONf_plane_restr0.0051651
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8544-2.95640.36471200.39352296X-RAY DIFFRACTION85
2.9564-3.07470.28721410.31772673X-RAY DIFFRACTION100
3.0747-3.21460.3151420.28872690X-RAY DIFFRACTION100
3.2146-3.38410.27051420.27062682X-RAY DIFFRACTION100
3.3841-3.5960.27521430.27152702X-RAY DIFFRACTION99
3.596-3.87360.25021420.2422704X-RAY DIFFRACTION99
3.8736-4.26310.22831420.20432696X-RAY DIFFRACTION99
4.2631-4.87950.22641440.19842744X-RAY DIFFRACTION99
4.8795-6.14560.23291460.21752772X-RAY DIFFRACTION100
6.1456-47.55310.22161520.18692866X-RAY DIFFRACTION99

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