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- PDB-8g44: Structure of HDAC6 zinc-finger ubiquitin binding domain in comple... -

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Basic information

Entry
Database: PDB / ID: 8g44
TitleStructure of HDAC6 zinc-finger ubiquitin binding domain in complex with 3-(3-(2-(benzylamino)-2-oxoethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propanoic acid
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 / negative regulation of aggrephagy / response to misfolded protein / positive regulation of protein oligomerization / type 2 mitophagy / negative regulation of protein-containing complex disassembly / peroxidase inhibitor activity / regulation of autophagy of mitochondrion ...negative regulation of hydrogen peroxide metabolic process / cellular response to topologically incorrect protein / polyubiquitinated misfolded protein transport / negative regulation of aggrephagy / response to misfolded protein / positive regulation of protein oligomerization / type 2 mitophagy / negative regulation of protein-containing complex disassembly / peroxidase inhibitor activity / regulation of autophagy of mitochondrion / erythrocyte enucleation / tubulin deacetylation / Cilium Assembly / protein-containing complex disassembly / collateral sprouting / regulation of establishment of protein localization / deacetylase activity / Transcriptional regulation by RUNX2 / tubulin deacetylase activity / lysosome localization / negative regulation of microtubule depolymerization / ATPase inhibitor activity / cilium disassembly / misfolded protein binding / protein deacetylation / positive regulation of type 2 mitophagy / dendritic spine morphogenesis / ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway / cytoplasmic ubiquitin ligase complex / regulation of androgen receptor signaling pathway / aggresome assembly / Transferases; Acyltransferases; Aminoacyltransferases / regulation of fat cell differentiation / histone deacetylase activity / cellular response to misfolded protein / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / aggresome / microtubule associated complex / positive regulation of intracellular estrogen receptor signaling pathway / Notch-HLH transcription pathway / negative regulation of gene expression, epigenetic / axonal transport of mitochondrion / RUNX2 regulates osteoblast differentiation / regulation of microtubule-based movement / histone deacetylase complex / cell leading edge / protein quality control for misfolded or incompletely synthesized proteins / dynein complex binding / positive regulation of epithelial cell migration / cilium assembly / regulation of macroautophagy / HSF1 activation / polyubiquitin modification-dependent protein binding / alpha-tubulin binding / negative regulation of protein-containing complex assembly / beta-tubulin binding / negative regulation of proteolysis / multivesicular body / axon cytoplasm / inclusion body / transcription corepressor binding / regulation of autophagy / actin filament organization / ubiquitin binding / regulation of protein stability / Late endosomal microautophagy / Hsp90 protein binding / intracellular protein transport / caveola / beta-catenin binding / NOTCH1 Intracellular Domain Regulates Transcription / protein destabilization / tau protein binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / epidermal growth factor receptor signaling pathway / histone deacetylase binding / cellular response to hydrogen peroxide / Chaperone Mediated Autophagy / Aggrephagy / protein polyubiquitination / ubiquitin protein ligase activity / cellular response to heat / actin binding / microtubule binding / microtubule / perikaryon / ciliary basal body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / axon / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / centrosome / dendrite / perinuclear region of cytoplasm / enzyme binding / zinc ion binding / nucleoplasm / nucleus
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-ZU9 / Protein deacetylase HDAC6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.55 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)12,4945
Polymers11,9331
Non-polymers5624
Water1,910106
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)40.950, 44.430, 56.130
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-ZU9 / 3-{3-[2-(benzylamino)-2-oxoethyl]-4-oxo-3,4-dihydroquinazolin-2-yl}propanoic acid


Mass: 365.383 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / 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: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN A200 / Detector: CCD / Date: Sep 27, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.55→33.08 Å / Num. obs: 15042 / % possible obs: 97.9 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.048 / Rpim(I) all: 0.02 / Rrim(I) all: 0.052 / Χ2: 0.91 / Net I/σ(I): 28.2 / Num. measured all: 100957
Reflection shellResolution: 1.55→1.58 Å / % possible obs: 94.6 % / Redundancy: 6.2 % / Rmerge(I) obs: 0.265 / Num. measured all: 4324 / Num. unique obs: 696 / CC1/2: 0.964 / Rpim(I) all: 0.115 / Rrim(I) all: 0.289 / Χ2: 1.02 / Net I/σ(I) obs: 7.9

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Processing

Software
NameVersionClassification
Aimlessdata scaling
REFMAC5.5refinement
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.55→33.08 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.937 / SU B: 1.083 / SU ML: 0.041 / Cross valid method: THROUGHOUT / ESU R: 0.076 / ESU R Free: 0.077 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19314 700 4.7 %RANDOM
Rwork0.16425 ---
obs0.16565 14341 97.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 9.851 Å2
Baniso -1Baniso -2Baniso -3
1--0.15 Å2-0 Å20 Å2
2--0.81 Å2-0 Å2
3----0.66 Å2
Refinement stepCycle: 1 / Resolution: 1.55→33.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms771 0 30 106 907
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.013840
X-RAY DIFFRACTIONr_bond_other_d0.0010.016710
X-RAY DIFFRACTIONr_angle_refined_deg1.9631.6421151
X-RAY DIFFRACTIONr_angle_other_deg1.591.61633
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.788598
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.13223.78437
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.65515107
X-RAY DIFFRACTIONr_dihedral_angle_4_deg0.32151
X-RAY DIFFRACTIONr_chiral_restr0.1190.299
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.021061
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02197
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_it1.130.914395
X-RAY DIFFRACTIONr_mcbond_other1.1280.913396
X-RAY DIFFRACTIONr_mcangle_it1.6671.368493
X-RAY DIFFRACTIONr_mcangle_other1.6831.371493
X-RAY DIFFRACTIONr_scbond_it1.671.004445
X-RAY DIFFRACTIONr_scbond_other1.6681.003446
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.4761.473659
X-RAY DIFFRACTIONr_long_range_B_refined3.65411.694948
X-RAY DIFFRACTIONr_long_range_B_other3.65711.71946
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.219 44 -
Rwork0.177 1015 -
obs--94.22 %

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