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- PDB-6ws5: Rational drug design of phenazopyridine derivatives as novel inhi... -

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Basic information

Entry
Database: PDB / ID: 6ws5
TitleRational drug design of phenazopyridine derivatives as novel inhibitors of Rev1-CT
Components
  • DNA polymerase zeta catalytic subunit
  • DNA repair protein REV1
  • Mitotic spindle assembly checkpoint protein MAD2B
KeywordsPROTEIN BINDING/Transferase / scaffold / complex / translesion synethesis / DNA damage response / DNA damage tolerance / PROTEIN BINDING / PROTEIN BINDING-Transferase complex
Function / homology
Function and homology information


somatic diversification of immunoglobulins involved in immune response / DNA damage response, signal transduction resulting in transcription / telomere maintenance in response to DNA damage / deoxycytidyl transferase activity / negative regulation of transcription regulatory region DNA binding / zeta DNA polymerase complex / positive regulation of isotype switching / positive regulation of extracellular matrix assembly / negative regulation of epithelial to mesenchymal transition / negative regulation of transcription by competitive promoter binding ...somatic diversification of immunoglobulins involved in immune response / DNA damage response, signal transduction resulting in transcription / telomere maintenance in response to DNA damage / deoxycytidyl transferase activity / negative regulation of transcription regulatory region DNA binding / zeta DNA polymerase complex / positive regulation of isotype switching / positive regulation of extracellular matrix assembly / negative regulation of epithelial to mesenchymal transition / negative regulation of transcription by competitive promoter binding / negative regulation of cell-cell adhesion mediated by cadherin / JUN kinase binding / negative regulation of ubiquitin protein ligase activity / negative regulation of double-strand break repair via homologous recombination / error-free translesion synthesis / mitotic spindle assembly checkpoint signaling / positive regulation of double-strand break repair via nonhomologous end joining / positive regulation of epithelial to mesenchymal transition / error-prone translesion synthesis / response to UV / Translesion synthesis by REV1 / Translesion synthesis by POLK / Translesion synthesis by POLI / actin filament organization / regulation of cell growth / Termination of translesion DNA synthesis / double-strand break repair via homologous recombination / negative regulation of canonical Wnt signaling pathway / negative regulation of DNA-binding transcription factor activity / negative regulation of protein catabolic process / DNA-templated DNA replication / spindle / double-strand break repair / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / positive regulation of peptidyl-serine phosphorylation / site of double-strand break / chromosome / 4 iron, 4 sulfur cluster binding / RNA polymerase II-specific DNA-binding transcription factor binding / DNA replication / damaged DNA binding / DNA-directed DNA polymerase / DNA-directed DNA polymerase activity / cell division / nucleotide binding / chromatin / nucleolus / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / metal ion binding / nucleus / cytoplasm
Similarity search - Function
DNA repair protein Rev1, C-terminal / Rev1, C-terminal domain superfamily / : / DNA repair protein REV1 C-terminal domain / Domain of unknown function DUF4683 / Domain of unknown function (DUF4683) / DNA polymerase zeta catalytic subunit / HUWE1/Rev1, ubiquitin binding region / Ubiquitin binding region / DNA repair protein Rev1 ...DNA repair protein Rev1, C-terminal / Rev1, C-terminal domain superfamily / : / DNA repair protein REV1 C-terminal domain / Domain of unknown function DUF4683 / Domain of unknown function (DUF4683) / DNA polymerase zeta catalytic subunit / HUWE1/Rev1, ubiquitin binding region / Ubiquitin binding region / DNA repair protein Rev1 / C4-type zinc-finger of DNA polymerase delta / C4-type zinc-finger of DNA polymerase delta / Mad2-like / HORMA domain / HORMA domain / HORMA domain profile. / HORMA domain superfamily / DNApol eta/Rev1, HhH motif / DNA polymerase family B, thumb domain / DNA polymerase family B signature. / DNA-directed DNA polymerase, family B, conserved site / DNA polymerase family B / DNA polymerase family B, exonuclease domain / DNA-directed DNA polymerase, family B, exonuclease domain / DNA-directed DNA polymerase, family B, multifunctional domain / DNA polymerase, palm domain superfamily / DNA polymerase type-B family / DNA-directed DNA polymerase, family B / BRCA1 C Terminus (BRCT) domain / DNA polymerase, Y-family, little finger domain / impB/mucB/samB family C-terminal domain / UmuC domain / DNA polymerase, Y-family, little finger domain superfamily / impB/mucB/samB family / UmuC domain profile. / breast cancer carboxy-terminal domain / BRCT domain profile. / BRCT domain / BRCT domain superfamily / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
Chem-U8M / DNA polymerase zeta catalytic subunit / DNA repair protein REV1 / Mitotic spindle assembly checkpoint protein MAD2B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.472 Å
AuthorsMcPherson, K.S. / Korzhnev, D.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA233959 United States
CitationJournal: Chemmedchem / Year: 2021
Title: Structure-Based Drug Design of Phenazopyridine Derivatives as Inhibitors of Rev1 Interactions in Translesion Synthesis.
Authors: McPherson, K.S. / Zaino, A.M. / Dash, R.C. / Rizzo, A.A. / Li, Y. / Hao, B. / Bezsonova, I. / Hadden, M.K. / Korzhnev, D.M.
History
DepositionApr 30, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 23, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 7, 2021Group: 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
Revision 1.2Oct 18, 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
HHH: DNA repair protein REV1
CCC: Mitotic spindle assembly checkpoint protein MAD2B
ZZZ: DNA polymerase zeta catalytic subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9944
Polymers42,7453
Non-polymers2491
Water181
1
CCC: Mitotic spindle assembly checkpoint protein MAD2B
ZZZ: DNA polymerase zeta catalytic subunit

HHH: DNA repair protein REV1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,9944
Polymers42,7453
Non-polymers2491
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_645-x+1,y-1/2,-z+1/21
Buried area4000 Å2
ΔGint-29 kcal/mol
Surface area15850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.019, 73.023, 85.554
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein DNA repair protein REV1 / / Alpha integrin-binding protein 80 / AIBP80 / Rev1-like terminal deoxycytidyl transferase


Mass: 11011.666 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: REV1, REV1L / Production host: Escherichia coli (E. coli)
References: UniProt: Q9UBZ9, Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases
#2: Protein Mitotic spindle assembly checkpoint protein MAD2B / Mitotic arrest deficient 2-like protein 2 / MAD2-like protein 2 / REV7 homolog / hREV7


Mass: 26101.236 Da / Num. of mol.: 1 / Mutation: R124A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAD2L2, MAD2B, REV7 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UI95
#3: Protein DNA polymerase zeta catalytic subunit / Protein reversionless 3-like / hREV3


Mass: 5632.319 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: REV3L, POLZ, REV3 / Production host: Escherichia coli (E. coli) / References: UniProt: O60673, DNA-directed DNA polymerase
#4: Chemical ChemComp-U8M / 3-[(Z)-(2,3-difluorophenyl)diazenyl]pyridine-2,6-diamine


Mass: 249.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C11H9F2N5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / 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

Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 162 mM triammonium citrate and 18% w/v PEG 3350

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Data collection

DiffractionMean temperature: 280 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Sep 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.47→29.508 Å / Num. obs: 11712 / % possible obs: 99.6 % / Redundancy: 6.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.028 / Rrim(I) all: 0.075 / Net I/σ(I): 13.7
Reflection shellResolution: 2.47→2.57 Å / Rmerge(I) obs: 0.784 / Mean I/σ(I) obs: 2 / Num. unique obs: 1260 / CC1/2: 0.823 / Rpim(I) all: 0.47 / Rrim(I) all: 0.857

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3vu7

3vu7


Resolution: 2.472→29.508 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.948 / Cross valid method: FREE R-VALUE / ESU R: 0.913 / ESU R Free: 0.288
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2375 620 5.311 %
Rwork0.2014 11053 -
all0.203 --
obs-11673 99.497 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 70 Å2
Baniso -1Baniso -2Baniso -3
1-3.385 Å20 Å20 Å2
2--0.161 Å20 Å2
3----3.546 Å2
Refinement stepCycle: LAST / Resolution: 2.472→29.508 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2546 0 18 1 2565
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0132611
X-RAY DIFFRACTIONr_bond_other_d0.0340.0172507
X-RAY DIFFRACTIONr_angle_refined_deg1.9241.6393541
X-RAY DIFFRACTIONr_angle_other_deg2.3441.5745830
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.7715311
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.57224.016127
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.46115489
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5271511
X-RAY DIFFRACTIONr_chiral_restr0.0970.2348
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022799
X-RAY DIFFRACTIONr_gen_planes_other0.0110.02481
X-RAY DIFFRACTIONr_nbd_refined0.2360.2558
X-RAY DIFFRACTIONr_symmetry_nbd_other0.230.22452
X-RAY DIFFRACTIONr_nbtor_refined0.1690.21223
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0780.21146
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1450.241
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1120.24
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.270.223
X-RAY DIFFRACTIONr_nbd_other0.2910.299
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2510.21
X-RAY DIFFRACTIONr_mcbond_it10.4967.1041256
X-RAY DIFFRACTIONr_mcbond_other10.4887.11255
X-RAY DIFFRACTIONr_mcangle_it13.92110.6211563
X-RAY DIFFRACTIONr_mcangle_other13.91810.6271564
X-RAY DIFFRACTIONr_scbond_it12.3158.0651355
X-RAY DIFFRACTIONr_scbond_other12.3118.0671356
X-RAY DIFFRACTIONr_scangle_it16.70211.691978
X-RAY DIFFRACTIONr_scangle_other16.69811.6921979
X-RAY DIFFRACTIONr_lrange_it19.49784.4622808
X-RAY DIFFRACTIONr_lrange_other19.49884.5012809
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.472-2.5360.285460.349779X-RAY DIFFRACTION96.1494
2.536-2.6050.364470.355780X-RAY DIFFRACTION100
2.605-2.6810.362390.334771X-RAY DIFFRACTION99.8767
2.681-2.7630.339320.325743X-RAY DIFFRACTION100
2.763-2.8540.528280.268721X-RAY DIFFRACTION100
2.854-2.9540.236330.219714X-RAY DIFFRACTION100
2.954-3.0650.245440.248665X-RAY DIFFRACTION100
3.065-3.190.309380.213649X-RAY DIFFRACTION100
3.19-3.3320.224360.189632X-RAY DIFFRACTION100
3.332-3.4940.248220.191593X-RAY DIFFRACTION100
3.494-3.6830.279320.216582X-RAY DIFFRACTION99.8374
3.683-3.9060.304370.194530X-RAY DIFFRACTION100
3.906-4.1750.202310.161517X-RAY DIFFRACTION99.6364
4.175-4.5080.183370.146471X-RAY DIFFRACTION99.8035
4.508-4.9370.196300.147437X-RAY DIFFRACTION98.9407
4.937-5.5180.167230.18401X-RAY DIFFRACTION99.5305
5.518-6.3670.265240.246360X-RAY DIFFRACTION99.7403
6.367-7.7870.269190.211310X-RAY DIFFRACTION100
7.787-10.9680.199160.152252X-RAY DIFFRACTION100
10.968-29.50.13870.209146X-RAY DIFFRACTION93.865

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