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- PDB-8g45: Structure of HDAC6 zinc-finger ubiquitin binding domain in comple... -

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Basic information

Entry
Database: PDB / ID: 8g45
TitleStructure of HDAC6 zinc-finger ubiquitin binding domain in complex with SGC-UBD253 chemical probe
ComponentsHistone deacetylase 6
KeywordsHYDROLASE/INHIBITOR / Inhibitor / chemical probe / HDAC6 / histone deacetylase / HYDROLASE / Structural Genomics / Structural Genomics Consortium / SGC / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of hydrogen peroxide metabolic process / cellular response to topologically incorrect protein / polyubiquitinated misfolded protein transport / positive regulation of cellular response to oxidative stress / erythrocyte enucleation / negative regulation of aggrephagy / positive regulation of cholangiocyte proliferation / response to misfolded protein / negative regulation of oxidoreductase activity / regulation of microtubule-based movement ...negative regulation of hydrogen peroxide metabolic process / cellular response to topologically incorrect protein / polyubiquitinated misfolded protein transport / positive regulation of cellular response to oxidative stress / erythrocyte enucleation / negative regulation of aggrephagy / positive regulation of cholangiocyte proliferation / response to misfolded protein / negative regulation of oxidoreductase activity / regulation of microtubule-based movement / parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization / negative regulation of protein-containing complex disassembly / protein-containing complex disassembly / negative regulation of axon extension involved in axon guidance / regulation of establishment of protein localization / positive regulation of tubulin deacetylation / tubulin deacetylation / Cilium Assembly / regulation of autophagy of mitochondrion / peptidyl-lysine deacetylation / tubulin deacetylase activity / collateral sprouting / Transcriptional regulation by RUNX2 / lysosome localization / negative regulation of protein acetylation / misfolded protein binding / negative regulation of microtubule depolymerization / ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway / protein deacetylation / cilium disassembly / response to growth factor / dendritic spine morphogenesis / histone deacetylase / aggresome assembly / regulation of androgen receptor signaling pathway / protein lysine deacetylase activity / positive regulation of signaling receptor activity / cellular response to misfolded protein / aggresome / cellular response to parathyroid hormone stimulus / positive regulation of dendrite morphogenesis / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / regulation of fat cell differentiation / microtubule associated complex / negative regulation of gene expression, epigenetic / histone deacetylase activity / response to corticosterone / dynein complex binding / axonal transport of mitochondrion / Notch-HLH transcription pathway / positive regulation of epithelial cell migration / beta-tubulin binding / cell leading edge / response to dexamethasone / protein quality control for misfolded or incompletely synthesized proteins / RUNX2 regulates osteoblast differentiation / histone deacetylase complex / response to immobilization stress / alpha-tubulin binding / cilium assembly / HSF1 activation / polyubiquitin modification-dependent protein binding / regulation of macroautophagy / negative regulation of protein-containing complex assembly / inclusion body / axon cytoplasm / response to amphetamine / multivesicular body / positive regulation of synaptic transmission, glutamatergic / transcription corepressor binding / ciliary basal body / ubiquitin binding / regulation of autophagy / caveola / negative regulation of proteolysis / actin filament organization / Late endosomal microautophagy / intracellular protein transport / Hsp90 protein binding / protein destabilization / regulation of protein stability / tau protein binding / NOTCH1 Intracellular Domain Regulates Transcription / beta-catenin binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / autophagy / histone deacetylase binding / Aggrephagy / Chaperone Mediated Autophagy / cellular response to hydrogen peroxide / protein polyubiquitination / positive regulation of peptidyl-serine phosphorylation / actin binding / cellular response to heat / microtubule binding / perikaryon / microtubule / RNA polymerase II cis-regulatory region sequence-specific DNA binding / axon
Similarity search - Function
Ubiquitin Carboxyl-terminal Hydrolase-like zinc finger / Zinc finger, UBP-type / Zn-finger in ubiquitin-hydrolases and other protein / Zinc finger UBP-type profile. / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-ZUE / Histone deacetylase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsHarding, R.J. / Franzoni, I. / Mann, M.K. / Szewczyk, M. / Mirabi, B. / Owens, D.D.G. / Ackloo, S. / Scheremetjew, A. / Juarez-Ornelas, K.A. / Sanichar, R. ...Harding, R.J. / Franzoni, I. / Mann, M.K. / Szewczyk, M. / Mirabi, B. / Owens, D.D.G. / Ackloo, S. / Scheremetjew, A. / Juarez-Ornelas, K.A. / Sanichar, R. / Baker, R.J. / Dank, C. / Brown, P.J. / Barsyte-Lovejoy, D. / Santhakumar, V. / Schapira, M. / Lautens, M. / Arrowsmith, C.H. / Structural Genomics Consortium (SGC)
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6.
Authors: Harding, R.J. / Franzoni, I. / Mann, M.K. / Szewczyk, M.M. / Mirabi, B. / Ferreira de Freitas, R. / Owens, D.D.G. / Ackloo, S. / Scheremetjew, A. / Juarez-Ornelas, K.A. / Sanichar, R. / ...Authors: Harding, R.J. / Franzoni, I. / Mann, M.K. / Szewczyk, M.M. / Mirabi, B. / Ferreira de Freitas, R. / Owens, D.D.G. / Ackloo, S. / Scheremetjew, A. / Juarez-Ornelas, K.A. / Sanichar, R. / Baker, R.J. / Dank, C. / Brown, P.J. / Barsyte-Lovejoy, D. / Santhakumar, V. / Schapira, M. / Lautens, M. / Arrowsmith, C.H.
History
DepositionFeb 8, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 16, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Histone deacetylase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,5595
Polymers11,9331
Non-polymers6264
Water1,00956
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.610, 44.910, 55.700
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 Histone deacetylase 6 / HD6


Mass: 11932.607 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC6, KIAA0901, JM21 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UBN7, histone deacetylase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-ZUE / 3-[8-chloro-3-(2-{[(2-methoxyphenyl)methyl]amino}-2-oxoethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]propanoic acid


Mass: 429.854 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20ClN3O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 56 / 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: 2.13 Å3/Da / Density % sol: 42.21 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 2 M sodium formate, 0.2 M sodium acetate pH4.6, 5 % ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 2, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.62→55.7 Å / Num. obs: 13460 / % possible obs: 99.7 % / Redundancy: 7.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.024 / Rrim(I) all: 0.066 / Χ2: 0.9 / Net I/σ(I): 14.6 / Num. measured all: 95583
Reflection shellResolution: 1.62→1.65 Å / % possible obs: 99.2 % / Redundancy: 7.5 % / Rmerge(I) obs: 0.586 / Num. measured all: 4881 / Num. unique obs: 652 / CC1/2: 0.923 / Rpim(I) all: 0.227 / Rrim(I) all: 0.629 / Χ2: 0.97 / Net I/σ(I) obs: 3.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
Aimlessdata scaling
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.62→34.96 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.967 / SU B: 1.782 / SU ML: 0.06 / Cross valid method: THROUGHOUT / ESU R: 0.08 / ESU R Free: 0.082 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19036 681 5.1 %RANDOM
Rwork0.16003 ---
obs0.16162 12739 99.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.165 Å2
Baniso -1Baniso -2Baniso -3
1--0.26 Å2-0 Å20 Å2
2--2.07 Å2-0 Å2
3----1.81 Å2
Refinement stepCycle: 1 / Resolution: 1.62→34.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms771 0 33 56 860
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.012831
X-RAY DIFFRACTIONr_bond_other_d0.0010.016719
X-RAY DIFFRACTIONr_angle_refined_deg1.6711.6161140
X-RAY DIFFRACTIONr_angle_other_deg1.5181.5991654
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.765598
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.19323.61136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.03815108
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.904151
X-RAY DIFFRACTIONr_chiral_restr0.1060.299
X-RAY DIFFRACTIONr_gen_planes_refined0.010.021056
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02194
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_it2.3242.916396
X-RAY DIFFRACTIONr_mcbond_other2.3212.921397
X-RAY DIFFRACTIONr_mcangle_it3.1834.359492
X-RAY DIFFRACTIONr_mcangle_other3.184.365493
X-RAY DIFFRACTIONr_scbond_it3.4683.205435
X-RAY DIFFRACTIONr_scbond_other3.4733.206433
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.1224.708648
X-RAY DIFFRACTIONr_long_range_B_refined5.96336.007961
X-RAY DIFFRACTIONr_long_range_B_other5.9735.922957
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.62→1.662 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.274 44 -
Rwork0.243 913 -
obs--99.38 %

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