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- PDB-5b8d: Crystal structure of a low occupancy fragment candidate (N-(4-Met... -

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Basic information

Entry
Database: PDB / ID: 5b8d
TitleCrystal structure of a low occupancy fragment candidate (N-(4-Methyl-1,3-thiazol-2-yl)propanamide) bound adjacent to the ubiquitin binding pocket of the HDAC6 zinc-finger domain
ComponentsHistone deacetylase 6
KeywordsHYDROLASE / HISTONE DEACETYLASE / HDAC / HDAC6 / FRAGMENT SCREENING / STRUCTURAL GENOMICS CONSORTIUM / SGC / DIAMOND I04-1 XCHEM / PANDDA
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 / negative regulation of aggrephagy / positive regulation of cholangiocyte proliferation / response to misfolded protein / positive regulation of protein oligomerization / negative regulation of axon extension involved in axon guidance / positive regulation of RIG-I signaling pathway ...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 / negative regulation of aggrephagy / positive regulation of cholangiocyte proliferation / response to misfolded protein / positive regulation of protein oligomerization / negative regulation of axon extension involved in axon guidance / positive regulation of RIG-I signaling pathway / type 2 mitophagy / negative regulation of protein-containing complex disassembly / peroxidase inhibitor activity / erythrocyte enucleation / regulation of autophagy of mitochondrion / Cilium Assembly / regulation of microtubule-based movement / tubulin deacetylation / protein-containing complex disassembly / regulation of establishment of protein localization / collateral sprouting / Transcriptional regulation by RUNX2 / tubulin deacetylase activity / negative regulation of microtubule depolymerization / lysosome localization / positive regulation of dendrite morphogenesis / ATPase inhibitor activity / cilium disassembly / histone deacetylase activity, hydrolytic mechanism / misfolded protein binding / ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway / dendritic spine morphogenesis / positive regulation of type 2 mitophagy / protein deacetylation / aggresome assembly / regulation of androgen receptor signaling pathway / regulation of mitochondrion organization / Transferases; Acyltransferases; Aminoacyltransferases / cellular response to misfolded protein / regulation of fat cell differentiation / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / aggresome / microtubule associated complex / cellular response to parathyroid hormone stimulus / response to corticosterone / histone deacetylase activity / positive regulation of intracellular estrogen receptor signaling pathway / response to dexamethasone / Notch-HLH transcription pathway / negative regulation of gene expression, epigenetic / axonal transport of mitochondrion / RUNX2 regulates osteoblast differentiation / cell leading edge / dynein complex binding / response to immobilization stress / protein quality control for misfolded or incompletely synthesized proteins / histone deacetylase complex / positive regulation of epithelial cell migration / cilium assembly / polyubiquitin modification-dependent protein binding / regulation of macroautophagy / HSF1 activation / alpha-tubulin binding / positive regulation of synaptic transmission, glutamatergic / beta-tubulin binding / negative regulation of protein-containing complex assembly / negative regulation of proteolysis / inclusion body / multivesicular body / antiviral innate immune response / axon cytoplasm / actin filament organization / response to amphetamine / epigenetic regulation of gene expression / ubiquitin binding / transcription corepressor binding / intracellular protein transport / Hsp90 protein binding / Late endosomal microautophagy / protein destabilization / beta-catenin binding / regulation of protein stability / caveola / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / tau protein binding / histone deacetylase binding / epidermal growth factor receptor signaling pathway / cellular response to hydrogen peroxide / Chaperone Mediated Autophagy / protein polyubiquitination / Aggrephagy / cellular response to heat / actin binding / perikaryon / microtubule binding / microtubule / regulation of autophagy
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
~{N}-(4-methyl-1,3-thiazol-2-yl)ethanamide / FORMIC ACID / Protein deacetylase HDAC6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.05 Å
AuthorsHarding, R.J. / Tempel, W. / Collins, P. / Pearce, N. / Brandao-Neto, J. / Douangamath, A. / Ravichandran, M. / Schapira, M. / Bountra, C. / Edwards, A.M. ...Harding, R.J. / Tempel, W. / Collins, P. / Pearce, N. / Brandao-Neto, J. / Douangamath, A. / Ravichandran, M. / Schapira, M. / Bountra, C. / Edwards, A.M. / von Delft, F. / Santhakumar, V. / Arrowsmith, C.M. / 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
DepositionJun 14, 2016Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Jul 27, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 21, 2018Group: Data collection / Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / diffrn_source / pdbx_struct_oper_list
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 / _diffrn_source.pdbx_synchrotron_site / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Feb 27, 2019Group: Data collection / Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.3Oct 12, 2022Group: Data collection / Database references / Other
Category: database_2 / diffrn_radiation_wavelength / pdbx_database_status
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.deposit_site
Revision 1.4Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)12,40044
Polymers11,9331
Non-polymers46743
Water1,42379
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area520 Å2
ΔGint-8 kcal/mol
Surface area5900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.434, 44.157, 56.549
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#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

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Non-polymers , 6 types, 122 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CH2O2
#4: Chemical ChemComp-6T4 / ~{N}-(4-methyl-1,3-thiazol-2-yl)ethanamide


Mass: 156.206 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8N2OS
#5: Chemical...
ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 36 / Source method: obtained synthetically
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.17 Å3/Da / Density % sol: 43.26 %
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: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 30, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 1.05→34.8 Å / Num. obs: 47523 / % possible obs: 97.4 % / Redundancy: 5.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.026 / Rrim(I) all: 0.064 / Net I/σ(I): 14.6 / Num. measured all: 257744
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) all% possible all
1.05-1.072.40.8931453918760.4780.6721.12579.1
5.76-33.425.70.03649.720713610.9970.0160.0499.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0151refinement
Aimless0.5.26data scaling
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementStarting model: pdbid 3C5K

3c5k


Resolution: 1.05→34.8 Å / Cor.coef. Fo:Fc: 0.98 / Cor.coef. Fo:Fc free: 0.977 / SU B: 0.733 / SU ML: 0.016 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.023 / ESU R Free: 0.023 / 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 in a public repository. Geometry restraints for the fragment candidate were prepared with GRADE. The methyl group of the fragment candidate was not resolved by electron density and was omitted from the model. Ambiguous difference density suggests some form of covalent modification of Cys1147.
RfactorNum. reflection% reflectionSelection details
Rfree0.1464 2178 4.6 %RANDOM
Rwork0.1283 ---
obs0.1291 45286 97.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 69.28 Å2 / Biso mean: 13.189 Å2 / Biso min: 6.88 Å2
Baniso -1Baniso -2Baniso -3
1--0.21 Å2-0 Å20 Å2
2--0.67 Å20 Å2
3----0.46 Å2
Refinement stepCycle: final / Resolution: 1.05→34.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms779 0 56 79 914
Biso mean--21.92 24.11 -
Num. residues----100
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.019918
X-RAY DIFFRACTIONr_bond_other_d0.0030.02822
X-RAY DIFFRACTIONr_angle_refined_deg1.5041.9011270
X-RAY DIFFRACTIONr_angle_other_deg1.09831897
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6245119
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.212544
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.04715131
X-RAY DIFFRACTIONr_dihedral_angle_4_deg6.14151
X-RAY DIFFRACTIONr_chiral_restr0.110.2135
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211124
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02235
X-RAY DIFFRACTIONr_mcbond_it0.8621.1438
X-RAY DIFFRACTIONr_mcbond_other0.8861.099439
X-RAY DIFFRACTIONr_mcangle_it1.1771.663555
X-RAY DIFFRACTIONr_rigid_bond_restr1.54331740
X-RAY DIFFRACTIONr_sphericity_free20.677529
X-RAY DIFFRACTIONr_sphericity_bonded5.86751792
LS refinement shellResolution: 1.052→1.08 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.305 152 -
Rwork0.295 2787 -
all-2939 -
obs--82.35 %

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