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- PDB-5h4j: Crystal structure of Human dUTPase in complex with N-[(1R)-1-[3-(... -

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Basic information

Entry
Database: PDB / ID: 5h4j
TitleCrystal structure of Human dUTPase in complex with N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamide
ComponentsDeoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Hydrolase / Hydrolase inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


pyrimidine deoxyribonucleotide binding / dUTP catabolic process / dUMP biosynthetic process / signaling receptor inhibitor activity / dUTP diphosphatase / dUTP diphosphatase activity / Interconversion of nucleotide di- and triphosphates / peroxisome proliferator activated receptor binding / nucleobase-containing compound metabolic process / dTMP biosynthetic process ...pyrimidine deoxyribonucleotide binding / dUTP catabolic process / dUMP biosynthetic process / signaling receptor inhibitor activity / dUTP diphosphatase / dUTP diphosphatase activity / Interconversion of nucleotide di- and triphosphates / peroxisome proliferator activated receptor binding / nucleobase-containing compound metabolic process / dTMP biosynthetic process / regulation of protein-containing complex assembly / liver development / response to organic cyclic compound / DNA replication / magnesium ion binding / mitochondrion / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / nucleus
Similarity search - Function
Deoxyuridine triphosphate nucleotidohydrolase / Deoxyuridine triphosphatase (dUTPase) / Deoxyuridine 5'-Triphosphate Nucleotidohydrolase; Chain A / dUTPase-like / dUTPase / dUTPase, trimeric / dUTPase-like superfamily / Distorted Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-FKM / IMIDAZOLE / Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsChong, K.T. / Miyahara, S. / Miyakoshi, H. / Fukuoka, M.
CitationJournal: Mol. Cancer Ther. / Year: 2018
Title: TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy.
Authors: Yano, W. / Yokogawa, T. / Wakasa, T. / Yamamura, K. / Fujioka, A. / Yoshisue, K. / Matsushima, E. / Miyahara, S. / Miyakoshi, H. / Taguchi, J. / Chong, K.T. / Takao, Y. / Fukuoka, M. / Matsuo, K.
History
DepositionNov 1, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 1, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 5, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Nov 8, 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4355
Polymers17,7711
Non-polymers6644
Water2,522140
1
A: Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial
hetero molecules

A: Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial
hetero molecules

A: Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,30615
Polymers53,3133
Non-polymers1,99212
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area11670 Å2
ΔGint-97 kcal/mol
Surface area15200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.645, 89.645, 89.645
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number198
Space group name H-MP213
Components on special symmetry positions
IDModelComponents
11A-391-

HOH

21A-416-

HOH

31A-417-

HOH

41A-418-

HOH

51A-424-

HOH

61A-435-

HOH

71A-440-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial / dUTPase / dUTP pyrophosphatase


Mass: 17771.068 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DUT / Production host: Escherichia coli (E. coli) / References: UniProt: P33316, dUTP diphosphatase

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Non-polymers , 5 types, 144 molecules

#2: Chemical ChemComp-FKM / N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamide


Mass: 451.536 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H29N3O6S
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 140 / 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: 3.38 Å3/Da / Density % sol: 63.59 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 15~20% PEG 4000, 50mM Tris, 150mM Sodium Acetate, 5mM Zn Acetate
PH range: 6.0~6.8

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Feb 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.8→51.76 Å / Num. obs: 22554 / % possible obs: 99.9 % / Redundancy: 8.4 % / Net I/σ(I): 24.9
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 7.9 % / Rmerge(I) obs: 0.237 / Mean I/σ(I) obs: 10.4 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
CrystalCleardata reduction
CrystalCleardata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1Q5U

1q5u


Resolution: 1.8→51.76 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.963 / SU B: 0.002 / SU ML: 0 / Cross valid method: THROUGHOUT / ESU R: 0.072 / ESU R Free: 0.074
RfactorNum. reflection% reflectionSelection details
Rfree0.17316 1144 5.1 %RANDOM
Rwork0.16942 ---
obs0.16961 21393 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 25.02 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 1.8→51.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms982 0 41 140 1163
LS refinement shellResolution: 1.799→1.846 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.245 89 -
Rwork0.216 1544 -
obs--100 %

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