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- PDB-5kh9: Crystal structure of a low occupancy fragment candidate (5-[(4-Is... -

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Basic information

Entry
Database: PDB / ID: 5kh9
TitleCrystal structure of a low occupancy fragment candidate (5-[(4-Isopropylphenyl)amino]-6-methyl-1,2,4-triazin-3(2H)-one) bound in 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 / erythrocyte enucleation / 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 ...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 / positive regulation of protein oligomerization / negative regulation of axon extension involved in axon guidance / regulation of microtubule-based movement / type 2 mitophagy / negative regulation of protein-containing complex disassembly / peroxidase inhibitor activity / regulation of establishment of protein localization / regulation of autophagy of mitochondrion / protein-containing complex disassembly / tubulin deacetylation / Cilium Assembly / collateral sprouting / tubulin deacetylase activity / Transcriptional regulation by RUNX2 / lysosome localization / negative regulation of microtubule depolymerization / positive regulation of dendrite morphogenesis / ATPase inhibitor activity / cilium disassembly / misfolded protein binding / ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway / positive regulation of type 2 mitophagy / histone H4K16 deacetylase activity, hydrolytic mechanism / histone H4K5 deacetylase activity, hydrolytic mechanism / histone H4K8 deacetylase activity, hydrolytic mechanism / histone H3K4 deacetylase activity, hydrolytic mechanism / histone H3K14 deacetylase activity, hydrolytic mechanism / dendritic spine morphogenesis / histone H4K12 deacetylase activity, hydrolytic mechanism / protein deacetylation / histone H3K9 deacetylase activity, hydrolytic mechanism / aggresome assembly / regulation of androgen receptor signaling pathway / regulation of mitochondrion organization / cellular response to misfolded protein / Transferases; Acyltransferases; Aminoacyltransferases / regulation of fat cell differentiation / protein lysine deacetylase activity / microtubule associated complex / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / aggresome / cellular response to parathyroid hormone stimulus / response to corticosterone / histone deacetylase activity / positive regulation of intracellular estrogen receptor signaling pathway / Notch-HLH transcription pathway / negative regulation of gene expression, epigenetic / axonal transport of mitochondrion / dynein complex binding / beta-tubulin binding / protein quality control for misfolded or incompletely synthesized proteins / RUNX2 regulates osteoblast differentiation / cell leading edge / response to dexamethasone / histone deacetylase complex / response to immobilization stress / positive regulation of epithelial cell migration / cilium assembly / polyubiquitin modification-dependent protein binding / alpha-tubulin binding / regulation of macroautophagy / HSF1 activation / negative regulation of protein-containing complex assembly / inclusion body / negative regulation of proteolysis / axon cytoplasm / multivesicular body / response to amphetamine / positive regulation of synaptic transmission, glutamatergic / epigenetic regulation of gene expression / ubiquitin binding / actin filament organization / transcription corepressor binding / intracellular protein transport / Hsp90 protein binding / Late endosomal microautophagy / protein destabilization / regulation of protein stability / beta-catenin binding / caveola / tau protein binding / NOTCH1 Intracellular Domain Regulates Transcription / cellular response to hydrogen peroxide / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / epidermal growth factor receptor signaling pathway / histone deacetylase binding / Chaperone Mediated Autophagy / protein polyubiquitination / Aggrephagy / actin binding / cellular response to heat
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-6T5 / FORMIC ACID / Protein deacetylase HDAC6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.07 Å
AuthorsHarding, R.J. / Tempel, W. / Ravichandran, M. / Collins, P. / Pearce, N. / Brandao-Neto, J. / Douangamath, A. / Schapira, M. / Bountra, C. / Edwards, A.M. ...Harding, R.J. / Tempel, W. / Ravichandran, M. / Collins, P. / Pearce, N. / Brandao-Neto, J. / Douangamath, A. / 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: RCSB / 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 1.3Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / 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)12,44240
Polymers11,9331
Non-polymers51039
Water1,42379
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area320 Å2
ΔGint-10 kcal/mol
Surface area6180 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, 118 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.: 1 / Source method: obtained synthetically / Formula: CH2O2
#4: Chemical ChemComp-6T5 / 6-methyl-5-[(4-propan-2-ylphenyl)amino]-2~{H}-1,2,4-triazin-3-one


Mass: 244.292 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H16N4O
#5: Chemical...
ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 33 / 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: Oct 2, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 1.07→34.81 Å / Num. obs: 46238 / % possible obs: 99.4 % / Redundancy: 5.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.028 / Rrim(I) all: 0.069 / Net I/σ(I): 13.5 / Num. measured all: 256160
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.07-1.13.10.9571.1196.6
4.79-34.815.60.04145199.8

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Processing

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

3c5k


Resolution: 1.07→34.8 Å / Cor.coef. Fo:Fc: 0.979 / Cor.coef. Fo:Fc free: 0.978 / SU B: 0.931 / SU ML: 0.02 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.025 / ESU R Free: 0.024 / 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. Ambiguous difference density suggests some form of covalent modification of Cys1147.
RfactorNum. reflection% reflectionSelection details
Rfree0.1503 2104 4.6 %RANDOM
Rwork0.1356 ---
obs0.1363 44074 99.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 193.07 Å2 / Biso mean: 14.755 Å2 / Biso min: 7.96 Å2
Baniso -1Baniso -2Baniso -3
1--0.75 Å2-0 Å2-0 Å2
2---0.4 Å2-0 Å2
3---1.15 Å2
Refinement stepCycle: final / Resolution: 1.07→34.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms778 0 58 79 915
Biso mean--32.92 28.67 -
Num. residues----100
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.019897
X-RAY DIFFRACTIONr_bond_other_d0.0030.02797
X-RAY DIFFRACTIONr_angle_refined_deg1.6151.9211241
X-RAY DIFFRACTIONr_angle_other_deg1.11131839
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3165114
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.08824.76242
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.43915122
X-RAY DIFFRACTIONr_dihedral_angle_4_deg8.94151
X-RAY DIFFRACTIONr_chiral_restr0.1140.2129
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0211139
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02228
X-RAY DIFFRACTIONr_mcbond_it1.4321.248430
X-RAY DIFFRACTIONr_mcbond_other1.431.248431
X-RAY DIFFRACTIONr_mcangle_it1.9781.881543
X-RAY DIFFRACTIONr_rigid_bond_restr2.23131694
X-RAY DIFFRACTIONr_sphericity_free33.838531
X-RAY DIFFRACTIONr_sphericity_bonded16.79151739
LS refinement shellResolution: 1.07→1.098 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.271 158 -
Rwork0.303 3111 -
all-3269 -
obs--96.26 %

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