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- PDB-8owz: Crystal structure of human Sirt2 in complex with a triazole-based... -

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Basic information

Entry
Database: PDB / ID: 8owz
TitleCrystal structure of human Sirt2 in complex with a triazole-based SirReal
ComponentsNAD-dependent protein deacetylase sirtuin-2
KeywordsHYDROLASE / Inhibitor / Sirtuin 2
Function / homology
Function and homology information


cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / cellular lipid catabolic process / negative regulation of striated muscle tissue development / : / NAD-dependent histone H4K16 deacetylase activity / positive regulation of meiotic nuclear division / positive regulation of attachment of spindle microtubules to kinetochore / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity ...cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / cellular lipid catabolic process / negative regulation of striated muscle tissue development / : / NAD-dependent histone H4K16 deacetylase activity / positive regulation of meiotic nuclear division / positive regulation of attachment of spindle microtubules to kinetochore / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / paranodal junction / tubulin deacetylation / lateral loop / NLRP3 inflammasome complex assembly / peptidyl-lysine deacetylation / mitotic nuclear membrane reassembly / negative regulation of NLRP3 inflammasome complex assembly / tubulin deacetylase activity / regulation of exit from mitosis / paranode region of axon / Schmidt-Lanterman incisure / positive regulation of fatty acid biosynthetic process / NAD-dependent protein lysine deacetylase activity / myelination in peripheral nervous system / rDNA heterochromatin formation / protein acetyllysine N-acetyltransferase / chromatin silencing complex / NAD-dependent histone deacetylase activity / regulation of phosphorylation / Initiation of Nuclear Envelope (NE) Reformation / protein deacetylation / juxtaparanode region of axon / positive regulation of oocyte maturation / protein lysine deacetylase activity / meiotic spindle / response to redox state / regulation of myelination / histone deacetylase activity / histone acetyltransferase binding / positive regulation of execution phase of apoptosis / negative regulation of fat cell differentiation / negative regulation of peptidyl-threonine phosphorylation / glial cell projection / positive regulation of cell division / NAD+ ADP-ribosyltransferase activity / NAD+ binding / subtelomeric heterochromatin formation / negative regulation of reactive oxygen species metabolic process / positive regulation of DNA binding / heterochromatin / heterochromatin formation / epigenetic regulation of gene expression / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / cellular response to epinephrine stimulus / substantia nigra development / centriole / negative regulation of autophagy / meiotic cell cycle / ubiquitin binding / negative regulation of protein catabolic process / mitotic spindle / autophagy / histone deacetylase binding / spindle / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / myelin sheath / chromosome / cellular response to oxidative stress / midbody / growth cone / cellular response to hypoxia / perikaryon / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA-binding transcription factor binding / microtubule / chromosome, telomeric region / regulation of cell cycle / cell division / innate immune response / negative regulation of DNA-templated transcription / centrosome / chromatin binding / nucleolus / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / mitochondrion / zinc ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Sirtuin, class I / Sirtuin, catalytic core small domain superfamily / Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / DHS-like NAD/FAD-binding domain superfamily
Similarity search - Domain/homology
(R,R)-2,3-BUTANEDIOL / Chem-KZU / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsFriedrich, F. / Zhang, L. / Schiedel, M. / Einsle, O. / Jung, M.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Research Foundation (DFG)SFB 992 Germany
German Research Foundation (DFG)295/18-1 Germany
CitationJournal: J.Med.Chem. / Year: 2023
Title: Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation.
Authors: Sinatra, L. / Vogelmann, A. / Friedrich, F. / Tararina, M.A. / Neuwirt, E. / Colcerasa, A. / Konig, P. / Toy, L. / Yesiloglu, T.Z. / Hilscher, S. / Gaitzsch, L. / Papenkordt, N. / Zhai, S. / ...Authors: Sinatra, L. / Vogelmann, A. / Friedrich, F. / Tararina, M.A. / Neuwirt, E. / Colcerasa, A. / Konig, P. / Toy, L. / Yesiloglu, T.Z. / Hilscher, S. / Gaitzsch, L. / Papenkordt, N. / Zhai, S. / Zhang, L. / Romier, C. / Einsle, O. / Sippl, W. / Schutkowski, M. / Gross, O. / Bendas, G. / Christianson, D.W. / Hansen, F.K. / Jung, M. / Schiedel, M.
History
DepositionApr 28, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 15, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,68111
Polymers34,4171
Non-polymers1,26410
Water4,143230
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1510 Å2
ΔGint4 kcal/mol
Surface area14590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)35.810, 73.463, 55.333
Angle α, β, γ (deg.)90.000, 95.340, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 1 molecules A

#1: Protein NAD-dependent protein deacetylase sirtuin-2 / Regulatory protein SIR2 homolog 2 / SIR2-like protein 2


Mass: 34416.727 Da / Num. of mol.: 1 / Fragment: UNP residues 56-356
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT2, SIR2L, SIR2L2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q8IXJ6, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides

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Non-polymers , 7 types, 240 molecules

#2: Chemical ChemComp-KZU / 2-(4,6-dimethylpyrimidin-2-yl)sulfanyl-N-[5-[[3-[[1-(2-methoxyethyl)-1,2,3-triazol-4-yl]methoxy]phenyl]methyl]-1,3-thiazol-2-yl]ethanamide / triazole-based sirtuin-rearranging ligand (SirReal)


Mass: 525.646 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27N7O3S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER / Bis-tris methane


Mass: 209.240 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#5: Chemical ChemComp-BU3 / (R,R)-2,3-BUTANEDIOL


Mass: 90.121 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O2
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#7: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 230 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.11 Å3/Da / Density % sol: 41.58 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 25 % PEG 3,350 , 0.1 M Bis-Tris pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Apr 6, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.65→55.09 Å / Num. obs: 33934 / % possible obs: 98.63 % / Redundancy: 6.7 % / Biso Wilson estimate: 20.21 Å2 / CC1/2: 0.998 / Net I/σ(I): 11.3
Reflection shellResolution: 1.65→1.68 Å / Num. unique obs: 1695 / CC1/2: 0.741

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.20.1-4487refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→55.09 Å / SU ML: 0.1775 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.1602
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1975 1714 5.06 %
Rwork0.1683 32189 -
obs0.1698 33903 98.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.04 Å2
Refinement stepCycle: LAST / Resolution: 1.65→55.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2354 0 80 230 2664
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00742581
X-RAY DIFFRACTIONf_angle_d0.93843489
X-RAY DIFFRACTIONf_chiral_restr0.054372
X-RAY DIFFRACTIONf_plane_restr0.0076458
X-RAY DIFFRACTIONf_dihedral_angle_d6.7797392
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.70.271400.23392699X-RAY DIFFRACTION99.06
1.7-1.750.25121510.21992645X-RAY DIFFRACTION99.01
1.75-1.820.27051500.22822690X-RAY DIFFRACTION98.99
1.82-1.890.24961600.19462681X-RAY DIFFRACTION99.37
1.89-1.970.22231300.17872732X-RAY DIFFRACTION99.72
1.97-2.080.23271390.18152671X-RAY DIFFRACTION99.5
2.08-2.210.19741490.18022698X-RAY DIFFRACTION99.3
2.21-2.380.23091330.16352465X-RAY DIFFRACTION90.97
2.38-2.620.20571420.17292660X-RAY DIFFRACTION97.97
2.62-30.19631570.17342718X-RAY DIFFRACTION99.97
3-3.780.18141390.15162726X-RAY DIFFRACTION99.83
3.78-55.090.14731240.1462804X-RAY DIFFRACTION99.86

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