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- PDB-5wpb: Crystal structure of fragment 3-(3-(pyridin-2-ylmethoxy)quinoxali... -

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Basic information

Entry
Database: PDB / ID: 5wpb
TitleCrystal structure of fragment 3-(3-(pyridin-2-ylmethoxy)quinoxalin-2-yl)propanoic acid bound in the ubiquitin binding pocket of the HDAC6 zinc-finger domain
ComponentsHistone deacetylase 6
Keywordshydrolase/hydrolase inhibitor / HISTONE DEACETYLASE / HDAC / HDAC6 / FRAGMENT SCREENING / STRUCTURAL GENOMICS CONSORTIUM / SGC / hydrolase-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 / type 2 mitophagy / negative regulation of protein-containing complex disassembly / negative regulation of axon extension involved in axon guidance / positive regulation of tubulin deacetylation / regulation of establishment of protein localization / protein-containing complex disassembly / regulation of autophagy of mitochondrion / tubulin deacetylation / Cilium Assembly / peptidyl-lysine deacetylation / collateral sprouting / tubulin deacetylase activity / Transcriptional regulation by RUNX2 / misfolded protein binding / lysosome localization / negative regulation of protein acetylation / negative regulation of microtubule depolymerization / ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway / cilium disassembly / protein deacetylation / response to growth factor / dendritic spine morphogenesis / histone deacetylase / regulation of androgen receptor signaling pathway / aggresome assembly / protein lysine deacetylase activity / positive regulation of signaling receptor activity / positive regulation of dendrite morphogenesis / cellular response to parathyroid hormone stimulus / cellular response to misfolded protein / aggresome / regulation of fat cell differentiation / microtubule associated complex / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / response to corticosterone / histone deacetylase activity / dynein complex binding / positive regulation of epithelial cell migration / negative regulation of gene expression, epigenetic / protein quality control for misfolded or incompletely synthesized proteins / Notch-HLH transcription pathway / axonal transport of mitochondrion / response to dexamethasone / cell leading edge / beta-tubulin binding / RUNX2 regulates osteoblast differentiation / histone deacetylase complex / response to immobilization stress / polyubiquitin modification-dependent protein binding / cilium assembly / HSF1 activation / alpha-tubulin binding / regulation of macroautophagy / negative regulation of protein-containing complex assembly / inclusion body / axon cytoplasm / response to amphetamine / multivesicular body / epigenetic regulation of gene expression / positive regulation of synaptic transmission, glutamatergic / transcription corepressor binding / ciliary basal body / ubiquitin binding / actin filament organization / regulation of autophagy / negative regulation of proteolysis / intracellular protein transport / Late endosomal microautophagy / Hsp90 protein binding / protein destabilization / regulation of protein stability / tau protein binding / caveola / NOTCH1 Intracellular Domain Regulates Transcription / histone deacetylase binding / autophagy / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / cellular response to hydrogen peroxide / beta-catenin binding / Aggrephagy / Chaperone Mediated Autophagy / 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
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 / Zinc/RING finger domain, C3HC4 (zinc finger) ...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 / Zinc/RING finger domain, C3HC4 (zinc finger) / Herpes Virus-1 / Ureohydrolase domain superfamily / Zinc finger, RING/FYVE/PHD-type / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-B8P / Histone deacetylase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.55 Å
AuthorsHarding, R.J. / Tempel, W. / Ferreira de Freitas, R. / Franzoni, I. / Ravichandran, M. / Lautens, M. / Santhakumar, V. / Schapira, M. / Bountra, C. / Edwards, A.M. ...Harding, R.J. / Tempel, W. / Ferreira de Freitas, R. / Franzoni, I. / Ravichandran, M. / Lautens, M. / Santhakumar, V. / Schapira, M. / Bountra, C. / Edwards, A.M. / Arrowsmith, C.H. / Structural Genomics Consortium (SGC)
CitationJournal: J. Med. Chem. / Year: 2017
Title: Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin.
Authors: Harding, R.J. / Ferreira de Freitas, R. / Collins, P. / Franzoni, I. / Ravichandran, M. / Ouyang, H. / Juarez-Ornelas, K.A. / Lautens, M. / Schapira, M. / von Delft, F. / Santhakumar, V. / Arrowsmith, C.H.
History
DepositionAug 4, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 23, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2019Group: Data collection / 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)12,13422
Polymers11,3221
Non-polymers81221
Water1,67593
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.850, 43.740, 55.760
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 Histone deacetylase 6 / HD6


Mass: 11321.949 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC6, KIAA0901, JM21 / Plasmid: PET28-LIC / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-CodonPlus(DE3)-RIL / 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-B8P / 3-{3-[(pyridin-2-yl)methoxy]quinoxalin-2-yl}propanoic acid


Mass: 309.319 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N3O3
#4: Chemical
ChemComp-UNX / UNKNOWN ATOM OR ION


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 93 / 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: 2.21 Å3/Da / Density % sol: 44.36 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 4.6
Details: 2M Na-formate, 0.2M Na-acetate pH4.6, 5% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN A200 / Detector: CCD / Date: Jul 7, 2016 / Details: A200
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.55→29.85 Å / Num. obs: 14896 / % possible obs: 99.2 % / Redundancy: 6.8 % / CC1/2: 1 / Rmerge(I) obs: 0.025 / Rpim(I) all: 0.01 / Rrim(I) all: 0.027 / Net I/σ(I): 69.9 / Num. measured all: 100583 / Scaling rejects: 0
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.55-1.586.40.0837060.9960.0360.09195.6
8.49-29.855.30.02111110.0090.02397.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
xia2data scaling
PDB_EXTRACT3.22data extraction
Aimlessdata scaling
RefinementResolution: 1.55→29.85 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.965 / SU B: 0.952 / SU ML: 0.036 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.067 / ESU R Free: 0.066
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY Ligand (B8P: 3-{3-[(pyridin-2-yl)methoxy]quinoxalin-2-yl}propanoic acid) occupancy was approximated by ...Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY Ligand (B8P: 3-{3-[(pyridin-2-yl)methoxy]quinoxalin-2-yl}propanoic acid) occupancy was approximated by manually setting B8P occupancy at 0.1 intervals and then performing cycles of Refmac refinement. The ligand occupancy which brought the B-factors of Tyr1184-OG and B8P-O2 closest in value after refinement, was determined to be the approximate occupancy. This is modelled as alternate conformation A. Residual density observed following ligand modelling and refinement may represent an alternative binding mode in which the quinoxaline ring makes pi-stacking interactions with Arg1155 and Trp1182 (as seen in comparable structures 5KH3, 5KH7, 5kH9 and 5WBN).
RfactorNum. reflection% reflectionSelection details
Rfree0.1621 722 4.8 %RANDOM
Rwork0.1427 ---
obs0.1437 14173 98.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 39.19 Å2 / Biso mean: 9.957 Å2 / Biso min: 5.13 Å2
Baniso -1Baniso -2Baniso -3
1--0.33 Å20 Å20 Å2
2--0.76 Å2-0 Å2
3----0.43 Å2
Refinement stepCycle: final / Resolution: 1.55→29.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms775 0 43 93 911
Biso mean--15.12 22.45 -
Num. residues----102
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.019847
X-RAY DIFFRACTIONr_bond_other_d0.0020.02701
X-RAY DIFFRACTIONr_angle_refined_deg1.5411.9041165
X-RAY DIFFRACTIONr_angle_other_deg1.09131635
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3765104
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.84124.57135
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.50415111
X-RAY DIFFRACTIONr_chiral_restr0.1130.2120
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211064
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02172
LS refinement shellResolution: 1.55→1.59 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.157 55 -
Rwork0.133 981 -
all-1036 -
obs--96.46 %

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