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- PDB-6cee: Crystal structure of fragment 3-(1-Methyl-2-oxo-1,2-dihydroquinox... -

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Basic information

Entry
Database: PDB / ID: 6cee
TitleCrystal structure of fragment 3-(1-Methyl-2-oxo-1,2-dihydroquinoxalin-3-yl)propionic acid bound in the ubiquitin binding pocket of the HDAC6 zinc-finger domain
ComponentsHistone deacetylase 6
KeywordsHYDROLASE / HISTONE DEACETYLASE / HDAC / HDAC6 / UBIQUITIN / STRUCTURAL GENOMICS CONSORTIUM / SGC
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 / protein-containing complex disassembly / positive regulation of tubulin deacetylation / regulation of establishment of protein localization / 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 / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / microtubule associated complex / histone deacetylase activity / response to corticosterone / protein quality control for misfolded or incompletely synthesized proteins / dynein complex binding / negative regulation of gene expression, epigenetic / positive regulation of epithelial cell migration / Notch-HLH transcription pathway / axonal transport of mitochondrion / response to dexamethasone / cell leading edge / beta-tubulin binding / RUNX2 regulates osteoblast differentiation / histone deacetylase complex / polyubiquitin modification-dependent protein binding / response to immobilization stress / 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 / protein destabilization / Late endosomal microautophagy / Hsp90 protein binding / regulation of protein stability / tau protein binding / caveola / NOTCH1 Intracellular Domain Regulates Transcription / beta-catenin binding / histone deacetylase binding / autophagy / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / cellular response to hydrogen peroxide / 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) / Ureohydrolase domain superfamily / Herpes Virus-1 / Zinc finger, RING/FYVE/PHD-type / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-EYM / Histone deacetylase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.55 Å
AuthorsHarding, R.J. / Halabelian, L. / Ferreira de Freitas, R. / Franzoni, I. / Ravichandran, M. / Lautens, M. / Santhakumar, V. / Schapira, M. / Bountra, C. / Edwards, A.M. ...Harding, R.J. / Halabelian, L. / Ferreira de Freitas, R. / Franzoni, I. / Ravichandran, M. / Lautens, M. / Santhakumar, V. / Schapira, M. / Bountra, C. / Edwards, A.M. / Arrowsmith, C.M. / Structural Genomics Consortium (SGC)
CitationJournal: J. Med. Chem. / Year: 2018
Title: Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors.
Authors: Ferreira de Freitas, R. / Harding, R.J. / Franzoni, I. / Ravichandran, M. / Mann, M.K. / Ouyang, H. / Lautens, M. / Santhakumar, V. / Arrowsmith, C.H. / Schapira, M.
History
DepositionFeb 11, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 28, 2018Provider: repository / Type: Initial release
Revision 1.1May 16, 2018Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 30, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 4, 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

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Assembly

Deposited unit
A: Histone deacetylase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,3619
Polymers11,9331
Non-polymers4288
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area5640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.720, 44.110, 55.910
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: 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 / Plasmid: pET28-lic / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) codon plus / 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-EYM / 3-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)propanoic acid


Mass: 232.235 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H12N2O3
#4: Chemical
ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 4 / Source method: obtained synthetically
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 2.09 Å3/Da / Density % sol: 41.07 % / Mosaicity: 0 °
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 4.6
Details: 2 M Na-formate, 0.2 M 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: Aug 24, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.55→30 Å / Num. obs: 15166 / % possible obs: 100 % / Redundancy: 6.7 % / CC1/2: 1 / Rmerge(I) obs: 0.037 / Rpim(I) all: 0.015 / Rrim(I) all: 0.04 / Net I/σ(I): 40.5 / Num. measured all: 101184 / Scaling rejects: 3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.55-1.5860.23146307660.9670.1020.2538.1100
8.49-29.925.20.02159011310.010.024102.198.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
Aimless0.6.2data scaling
PDB_EXTRACT3.24data extraction
xia2data reduction
RefinementStarting model: pdbid 5KH3

5kh3


Resolution: 1.55→30 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.959 / SU B: 1.024 / SU ML: 0.038 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.069 / ESU R Free: 0.067 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: Users of this crystal structure: verify our intepretion of the electron density. Amplitudes and unmerged intensities are included with this deposition. Diffraction images will be deposited ...Details: Users of this crystal structure: verify our intepretion of the electron density. Amplitudes and unmerged intensities are included with this deposition. Diffraction images will be deposited at a later date in a public repository. Geometry restraints for the ligand were prepared with GRADE.
RfactorNum. reflection% reflectionSelection details
Rfree0.1694 728 4.8 %RANDOM
Rwork0.153 ---
obs0.1538 14437 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 36.3 Å2 / Biso mean: 12.359 Å2 / Biso min: 6.93 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å20 Å20 Å2
2--0.7 Å2-0 Å2
3----0.64 Å2
Refinement stepCycle: final / Resolution: 1.55→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms777 0 24 87 888
Biso mean--19.92 22.09 -
Num. residues----100
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.019845
X-RAY DIFFRACTIONr_bond_other_d0.0020.02700
X-RAY DIFFRACTIONr_angle_refined_deg1.6751.9161161
X-RAY DIFFRACTIONr_angle_other_deg1.1723.011621
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5855101
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.63324.32437
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.99415110
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.323151
X-RAY DIFFRACTIONr_chiral_restr0.1240.2118
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211012
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02170
LS refinement shellResolution: 1.55→1.59 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.163 54 -
Rwork0.154 1050 -
all-1104 -
obs--99.82 %

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