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- PDB-5tus: Potent competitive inhibition of human ribonucleotide reductase b... -

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Basic information

Entry
Database: PDB / ID: 5tus
TitlePotent competitive inhibition of human ribonucleotide reductase by a novel non-nucleoside small molecule
ComponentsRibonucleoside-diphosphate reductase large subunit
KeywordsOXIDOREDUCTASE / Ribonucleotide Reductase / small molecule inhibitor / active site inhibitor / competitive inhibitor
Function / homology
Function and homology information


ribonucleoside-diphosphate reductase activity / pyrimidine nucleobase metabolic process / cell proliferation in forebrain / ribonucleoside diphosphate metabolic process / positive regulation of G0 to G1 transition / 2'-deoxyribonucleotide biosynthetic process / mitochondrial DNA replication / ribonucleoside-diphosphate reductase complex / ribonucleoside-diphosphate reductase / ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor ...ribonucleoside-diphosphate reductase activity / pyrimidine nucleobase metabolic process / cell proliferation in forebrain / ribonucleoside diphosphate metabolic process / positive regulation of G0 to G1 transition / 2'-deoxyribonucleotide biosynthetic process / mitochondrial DNA replication / ribonucleoside-diphosphate reductase complex / ribonucleoside-diphosphate reductase / ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor / Interconversion of nucleotide di- and triphosphates / deoxyribonucleotide biosynthetic process / protein heterotetramerization / response to ionizing radiation / DNA synthesis involved in DNA repair / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of G2/M transition of mitotic cell cycle / cell projection / male gonad development / disordered domain specific binding / retina development in camera-type eye / nuclear envelope / DNA repair / neuronal cell body / mitochondrion / ATP binding / identical protein binding / cytosol
Similarity search - Function
Ribonucleotide reductase, class I , alpha subunit / Ribonucleotide reductase large subunit signature. / Ribonucleoside-diphosphate reductase large subunit / ATP-cone domain / ATP cone domain / ATP-cone domain profile. / Ribonucleotide reductase R1 subunit, N-terminal / Ribonucleotide reductase large subunit, N-terminal / Ribonucleotide reductase, all-alpha domain / Ribonucleotide reductase large subunit, C-terminal / Ribonucleotide reductase, barrel domain
Similarity search - Domain/homology
Chem-7LL / THYMIDINE-5'-TRIPHOSPHATE / Ribonucleoside-diphosphate reductase large subunit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.66 Å
AuthorsMohammed, F.A. / Alam, I. / Dealwis, C.G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM100887 United States
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2017
Title: Potent competitive inhibition of human ribonucleotide reductase by a nonnucleoside small molecule.
Authors: Ahmad, M.F. / Alam, I. / Huff, S.E. / Pink, J. / Flanagan, S.A. / Shewach, D. / Misko, T.A. / Oleinick, N.L. / Harte, W.E. / Viswanathan, R. / Harris, M.E. / Dealwis, C.G.
History
DepositionNov 7, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 2, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 16, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ribonucleoside-diphosphate reductase large subunit
B: Ribonucleoside-diphosphate reductase large subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)181,6777
Polymers180,3582
Non-polymers1,3195
Water59433
1
A: Ribonucleoside-diphosphate reductase large subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,6853
Polymers90,1791
Non-polymers5062
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ribonucleoside-diphosphate reductase large subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,9924
Polymers90,1791
Non-polymers8133
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5010 Å2
ΔGint-38 kcal/mol
Surface area52650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.516, 114.282, 220.361
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 Ribonucleoside-diphosphate reductase large subunit / Ribonucleoside-diphosphate reductase subunit M1 / Ribonucleotide reductase large subunit


Mass: 90179.023 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: NSAAH (Naphthyl Salicyl Acyl Hydrazone) / Source: (gene. exp.) Homo sapiens (human) / Gene: RRM1, RR1 / Production host: Escherichia coli (E. coli)
References: UniProt: P23921, ribonucleoside-diphosphate reductase
#2: Chemical ChemComp-TTP / THYMIDINE-5'-TRIPHOSPHATE


Mass: 482.168 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N2O14P3
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-7LL / 2-hydroxy-N'-[(Z)-(2-hydroxynaphthalen-1-yl)methylidene]benzohydrazide


Mass: 306.315 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C18H14N2O3
#5: 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: 2.43 Å3/Da / Density % sol: 49.31 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.9
Details: 0.1 M Tris-HCl pH 7.9, 0.2 M LiSO4, 19% PEG 3350, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.66→110.18 Å / Num. obs: 48650 / % possible obs: 98.65 % / Redundancy: 5.4 % / Net I/σ(I): 9

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementResolution: 2.66→110.18 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.923 / Cross valid method: THROUGHOUT / ESU R: 1.378 / ESU R Free: 0.332 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24967 1998 3.9 %RANDOM
Rwork0.19911 ---
obs0.20108 48650 98.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 56.36 Å2
Baniso -1Baniso -2Baniso -3
1-5.09 Å2-0 Å20 Å2
2---2.09 Å2-0 Å2
3----3 Å2
Refinement stepCycle: 1 / Resolution: 2.66→110.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11597 0 83 33 11713
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.01911934
X-RAY DIFFRACTIONr_bond_other_d00.0211349
X-RAY DIFFRACTIONr_angle_refined_deg1.7191.96516175
X-RAY DIFFRACTIONr_angle_other_deg3.685326134
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.44751445
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.86124.49539
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.626152108
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7921560
X-RAY DIFFRACTIONr_chiral_restr0.0910.21790
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213358
X-RAY DIFFRACTIONr_gen_planes_other0.0110.022725
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.9655.4175799
X-RAY DIFFRACTIONr_mcbond_other3.9625.4155797
X-RAY DIFFRACTIONr_mcangle_it5.8838.1227237
X-RAY DIFFRACTIONr_mcangle_other5.8838.1237238
X-RAY DIFFRACTIONr_scbond_it4.6115.8286135
X-RAY DIFFRACTIONr_scbond_other4.615.8286136
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.0068.5598939
X-RAY DIFFRACTIONr_long_range_B_refined9.14463.57313548
X-RAY DIFFRACTIONr_long_range_B_other9.14263.57313542
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.66→2.729 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.445 146 -
Rwork0.409 3559 -
obs--99.44 %

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