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- PDB-6ojv: Crystal structure of human thymidylate synthase delta(7-29) in co... -

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Basic information

Entry
Database: PDB / ID: 6ojv
TitleCrystal structure of human thymidylate synthase delta(7-29) in complex with dUMP and 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-L-glutamic acid
ComponentsThymidylate synthase,Thymidylate synthase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / TS / TS-DHFR / 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-2XB / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.593 Å
AuthorsCzyzyk, D.J. / Anderson, K.S. / Valhondo, M. / Jorgensen, W.L.
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: Febs Lett. / Year: 2019
Title: Understanding the structural basis of species selective, stereospecific inhibition for Cryptosporidium and human thymidylate synthase.
Authors: Czyzyk, D.J. / Valhondo, M. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionApr 12, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 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,Thymidylate synthase
A: Thymidylate synthase,Thymidylate synthase
C: Thymidylate synthase,Thymidylate synthase
D: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,64312
Polymers132,7564
Non-polymers2,8868
Water59433
1
B: Thymidylate synthase,Thymidylate synthase
C: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8216
Polymers66,3782
Non-polymers1,4434
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Thymidylate synthase,Thymidylate synthase
D: Thymidylate synthase,Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8216
Polymers66,3782
Non-polymers1,4434
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5540 Å2
ΔGint-28 kcal/mol
Surface area20020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)154.950, 103.033, 109.211
Angle α, β, γ (deg.)90.00, 128.92, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein
Thymidylate synthase,Thymidylate synthase / TSase


Mass: 33189.070 Da / Num. of mol.: 4 / Fragment: residues 30-313
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: isolated from a natural source / Formula: C9H13N2O8P
#3: Chemical
ChemComp-2XB / N-{4-[(2-amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzoyl}-L-glutamic acid


Mass: 413.384 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H19N5O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / 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: 2.6 Å3/Da / Density % sol: 52.7 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: Well solution 5% PEG 8000, 40% MPD, and 0.1M Na cacodylate 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: Jul 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.59→50 Å / Num. obs: 41155 / % possible obs: 98.7 % / Redundancy: 6.6 % / CC1/2: 0.996 / Rsym value: 0.141 / Net I/σ(I): 12.75
Reflection shellResolution: 2.59→2.75 Å / Redundancy: 6.4 % / Mean I/σ(I) obs: 1.44 / Num. unique obs: 6486 / CC1/2: 0.807 / Rsym value: 1.16 / % possible all: 97.1

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HZW

1hzw


Resolution: 2.593→48.556 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 35.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2688 2051 5 %
Rwork0.2402 --
obs0.2417 41049 98.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.593→48.556 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8957 0 200 33 9190
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029397
X-RAY DIFFRACTIONf_angle_d0.51112780
X-RAY DIFFRACTIONf_dihedral_angle_d9.0445446
X-RAY DIFFRACTIONf_chiral_restr0.041366
X-RAY DIFFRACTIONf_plane_restr0.0041653
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5933-2.65360.53031270.46022423X-RAY DIFFRACTION93
2.6536-2.720.49871370.42092595X-RAY DIFFRACTION99
2.72-2.79350.39381350.36922583X-RAY DIFFRACTION98
2.7935-2.87570.3861350.33712572X-RAY DIFFRACTION99
2.8757-2.96850.37961360.3392589X-RAY DIFFRACTION100
2.9685-3.07460.39541370.33322617X-RAY DIFFRACTION100
3.0746-3.19770.37921400.3252641X-RAY DIFFRACTION100
3.1977-3.34320.36251370.30922603X-RAY DIFFRACTION100
3.3432-3.51940.32551360.28762599X-RAY DIFFRACTION99
3.5194-3.73980.29911370.26452598X-RAY DIFFRACTION99
3.7398-4.02850.28791380.24072618X-RAY DIFFRACTION99
4.0285-4.43360.18451370.18492609X-RAY DIFFRACTION99
4.4336-5.07460.17971380.17122631X-RAY DIFFRACTION100
5.0746-6.39120.25751400.21282647X-RAY DIFFRACTION100
6.3912-48.5640.16751410.16782673X-RAY DIFFRACTION99

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