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- PDB-6hoy: Human Sirt6 in complex with ADP-ribose and the inhibitor trichost... -

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Basic information

Entry
Database: PDB / ID: 6hoy
TitleHuman Sirt6 in complex with ADP-ribose and the inhibitor trichostatin A
ComponentsNAD-dependent protein deacetylase sirtuin-6
KeywordsHYDROLASE / Deacylase / Inhibitor / Hydroxamate / Non-competitive / Isoform-selective
Function / homology
Function and homology information


NAD-dependent histone H3K56 deacetylase activity / NAD-dependent histone H3K18 deacetylase activity / ketone biosynthetic process / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / regulation of lipid catabolic process / NAD+- protein-lysine ADP-ribosyltransferase activity / chromosome, subtelomeric region / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity ...NAD-dependent histone H3K56 deacetylase activity / NAD-dependent histone H3K18 deacetylase activity / ketone biosynthetic process / NAD-dependent histone H3K9 deacetylase activity / protein delipidation / regulation of lipid catabolic process / NAD+- protein-lysine ADP-ribosyltransferase activity / chromosome, subtelomeric region / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / pericentric heterochromatin formation / NAD+-protein-arginine ADP-ribosyltransferase activity / positive regulation of protein localization to chromatin / DNA damage sensor activity / positive regulation of stem cell differentiation / positive regulation of blood vessel branching / NAD-dependent protein lysine deacetylase activity / retrotransposon silencing / protein localization to site of double-strand break / protein acetyllysine N-acetyltransferase / cardiac muscle cell differentiation / positive regulation of chondrocyte proliferation / positive regulation of telomere maintenance / NAD-dependent histone deacetylase activity / protein deacetylation / negative regulation of glucose import / TORC2 complex binding / lncRNA binding / negative regulation of glycolytic process / negative regulation of protein localization to chromatin / DNA repair-dependent chromatin remodeling / positive regulation of double-strand break repair / positive regulation of vascular endothelial cell proliferation / regulation of double-strand break repair via homologous recombination / negative regulation of gene expression, epigenetic / negative regulation of protein import into nucleus / positive regulation of stem cell population maintenance / positive regulation of stem cell proliferation / regulation of protein secretion / negative regulation of transcription elongation by RNA polymerase II / site of DNA damage / NAD+-protein ADP-ribosyltransferase activity / negative regulation of cellular senescence / subtelomeric heterochromatin formation / regulation of lipid metabolic process / Transferases; Glycosyltransferases; Pentosyltransferases / NAD+ ADP-ribosyltransferase activity / NAD+ binding / nucleosome binding / positive regulation of fat cell differentiation / negative regulation of gluconeogenesis / pericentric heterochromatin / regulation of protein localization to plasma membrane / response to UV / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / nucleotidyltransferase activity / positive regulation of protein export from nucleus / determination of adult lifespan / circadian regulation of gene expression / protein destabilization / base-excision repair / regulation of circadian rhythm / positive regulation of insulin secretion / chromatin DNA binding / Pre-NOTCH Transcription and Translation / transcription corepressor activity / double-strand break repair / positive regulation of fibroblast proliferation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / glucose homeostasis / site of double-strand break / positive regulation of cold-induced thermogenesis / Processing of DNA double-strand break ends / damaged DNA binding / chromatin remodeling / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / chromatin binding / chromatin / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / protein homodimerization activity / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
Rubrerythrin, domain 2 - #200 / Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain / Rubrerythrin, domain 2 / DHS-like NAD/FAD-binding domain superfamily / Single Sheet / Rossmann fold ...Rubrerythrin, domain 2 - #200 / Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain / Rubrerythrin, domain 2 / DHS-like NAD/FAD-binding domain superfamily / Single Sheet / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-AR6 / TRICHOSTATIN A / NAD-dependent protein deacylase sirtuin-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsYou, W. / Steegborn, C.
CitationJournal: J.Med.Chem. / Year: 2018
Title: Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development.
Authors: You, W. / Steegborn, C.
History
DepositionSep 18, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 14, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2019Group: Data collection / Database references
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-6
B: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,36420
Polymers67,2632
Non-polymers3,10118
Water5,999333
1
A: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,19910
Polymers33,6321
Non-polymers1,5689
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: NAD-dependent protein deacetylase sirtuin-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,16510
Polymers33,6321
Non-polymers1,5349
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)91.291, 91.291, 143.681
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63
Components on special symmetry positions
IDModelComponents
11A-680-

HOH

21B-953-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1113A10 - 297
2113B10 - 297

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.347215, -0.93777, 0.005404), (-0.937748, -0.347247, -0.006931), (0.008376, -0.002661, -0.999961)-0.16359, 0.30883, 61.28952

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein NAD-dependent protein deacetylase sirtuin-6 / Regulatory protein SIR2 homolog 6 / SIR2-like protein 6


Mass: 33631.594 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT6, SIR2L6 / Plasmid: pET151-D-TOPO / Production host: Escherichia coli (E. coli) / Variant (production host): Rosetta2 (DE3) pLysS
References: UniProt: Q8N6T7, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides

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Non-polymers , 7 types, 351 molecules

#2: Chemical ChemComp-AR6 / [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE / Adenosine-5-Diphosphoribose


Mass: 559.316 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H23N5O14P2
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#7: Chemical ChemComp-TSN / TRICHOSTATIN A / 7-[4-(DIMETHYLAMINO)PHENYL]-N-HYDROXY-4,6-DIMETHYL-7-OXO-2,4-HEPTADIENAMIDE / Trichostatin A


Mass: 302.368 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H22N2O3 / Comment: antifungal, antibiotic*YM
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 333 / 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: 2.62 Å3/Da / Density % sol: 53.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.7
Details: 1.6 M (NH4)2SO4, 10% PEG 400, and Bis-Tris buffer pH 5.7
PH range: 5.7-6.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.684
11-K, -H, -L20.316
ReflectionResolution: 1.7→47.89 Å / Num. obs: 74416 / % possible obs: 99.9 % / Observed criterion σ(I): 0.87 / Redundancy: 11.4 % / Biso Wilson estimate: 34.27 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.15 / Net I/σ(I): 10.56
Reflection shellResolution: 1.7→1.8 Å / Redundancy: 11.6 % / Mean I/σ(I) obs: 0.87 / Num. unique obs: 11954 / CC1/2: 0.436 / Rrim(I) all: 2.47 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MF6

5mf6


Resolution: 1.7→45.65 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.966 / SU B: 1.26 / SU ML: 0.044 / Cross valid method: THROUGHOUT / ESU R: 0.017 / ESU R Free: 0.018 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18465 2122 2.9 %RANDOM
Rwork0.15441 ---
obs0.15526 72292 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 34.477 Å2
Baniso -1Baniso -2Baniso -3
1--12.43 Å2-0 Å2-0 Å2
2---12.43 Å2-0 Å2
3---24.87 Å2
Refinement stepCycle: 1 / Resolution: 1.7→45.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4342 0 191 333 4866
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0134663
X-RAY DIFFRACTIONr_bond_other_d0.0040.0174414
X-RAY DIFFRACTIONr_angle_refined_deg2.1861.6616332
X-RAY DIFFRACTIONr_angle_other_deg1.4051.59110214
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0065565
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.8319.753243
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.32615773
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2691550
X-RAY DIFFRACTIONr_chiral_restr0.1070.2596
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.025098
X-RAY DIFFRACTIONr_gen_planes_other0.0070.02990
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_it3.643.3112242
X-RAY DIFFRACTIONr_mcbond_other3.6373.312241
X-RAY DIFFRACTIONr_mcangle_it4.4654.9672801
X-RAY DIFFRACTIONr_mcangle_other4.4644.9682802
X-RAY DIFFRACTIONr_scbond_it4.5463.8632421
X-RAY DIFFRACTIONr_scbond_other4.5463.8652422
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.3875.5923528
X-RAY DIFFRACTIONr_long_range_B_refined8.20939.7354983
X-RAY DIFFRACTIONr_long_range_B_other8.21339.6294943
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
2615loose positional0.095
1599tight thermal4.120.5
2615loose thermal4.4410
LS refinement shellResolution: 1.699→1.743 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.334 158 -
Rwork0.326 5271 -
obs--99.05 %

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