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- PDB-5y5n: Crystal structure of human Sirtuin 2 in complex with a selective ... -

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Basic information

Entry
Database: PDB / ID: 5y5n
TitleCrystal structure of human Sirtuin 2 in complex with a selective inhibitor
ComponentsNAD-dependent protein deacetylase sirtuin-2
KeywordsHYDROLASE/INHIBITOR / Pseudopeptides / Anticancer activity / Neurite outgrowth / HYDROLASE-INHIBITOR complex
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 / negative regulation of satellite cell differentiation / positive regulation of meiotic nuclear division / NAD-dependent histone H4K16 deacetylase activity / 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 / negative regulation of satellite cell differentiation / positive regulation of meiotic nuclear division / NAD-dependent histone H4K16 deacetylase activity / 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 / NAD-dependent protein lysine deacetylase activity / positive regulation of fatty acid biosynthetic process / myelination in peripheral nervous system / rDNA heterochromatin formation / protein acetyllysine N-acetyltransferase / chromatin silencing complex / NAD-dependent histone deacetylase activity / Initiation of Nuclear Envelope (NE) Reformation / protein deacetylation / regulation of phosphorylation / positive regulation of oocyte maturation / juxtaparanode region of axon / protein lysine deacetylase activity / meiotic spindle / response to redox state / regulation of myelination / histone acetyltransferase binding / histone deacetylase activity / positive regulation of DNA binding / negative regulation of fat cell differentiation / negative regulation of peptidyl-threonine phosphorylation / positive regulation of execution phase of apoptosis / glial cell projection / positive regulation of cell division / NAD+-protein poly-ADP-ribosyltransferase activity / NAD+ binding / subtelomeric heterochromatin formation / negative regulation of reactive oxygen species metabolic process / heterochromatin / cellular response to epinephrine stimulus / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / substantia nigra development / centriole / epigenetic regulation of gene expression / negative regulation of autophagy / meiotic cell cycle / ubiquitin binding / negative regulation of protein catabolic process / heterochromatin formation / mitotic spindle / histone deacetylase binding / autophagy / spindle / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / myelin sheath / chromosome / cellular response to oxidative stress / midbody / cellular response to hypoxia / growth cone / 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 / SIR2/SIRT2 'Small Domain' / SIR2/SIRT2 'Small Domain' / Sirtuin, catalytic core small domain superfamily / : / Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain ...Sirtuin, class I / SIR2/SIRT2 'Small Domain' / SIR2/SIRT2 'Small Domain' / Sirtuin, catalytic core small domain superfamily / : / Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain / DHS-like NAD/FAD-binding domain superfamily / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
2-[[3-(2-phenylethoxy)phenyl]amino]benzamide / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsMellini, P. / Itoh, Y. / Tsumoto, H. / Li, Y. / Suzuki, M. / Tokuda, N. / Kakizawa, T. / Miura, Y. / Takeuchi, J. / Lahtela-Kakkonen, M. / Suzuki, T.
CitationJournal: Chem Sci / Year: 2017
Title: Potent mechanism-based sirtuin-2-selective inhibition by anin situ-generated occupant of the substrate-binding site, "selectivity pocket" and NAD+-binding site.
Authors: Mellini, P. / Itoh, Y. / Tsumoto, H. / Li, Y. / Suzuki, M. / Tokuda, N. / Kakizawa, T. / Miura, Y. / Takeuchi, J. / Lahtela-Kakkonen, M. / Suzuki, T.
History
DepositionAug 9, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 6, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2343
Polymers37,8361
Non-polymers3982
Water1,838102
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14880 Å2
Unit cell
Length a, b, c (Å)50.850, 57.980, 124.532
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 NAD-dependent protein deacetylase sirtuin-2 / Regulatory protein SIR2 homolog 2 / SIR2-like protein 2


Mass: 37836.387 Da / Num. of mol.: 1
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
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-8NO / 2-[[3-(2-phenylethoxy)phenyl]amino]benzamide


Mass: 332.396 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 102 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsGS residues of N terminal are rest of thrombin recognition sequence. From LYS289 to LYS312 are ...GS residues of N terminal are rest of thrombin recognition sequence. From LYS289 to LYS312 are missing and in this region, the residues LGETPFDDIAT from Sir2 homolog (PDB ID : 3JR3) are inserted.

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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: 2.65 Å3/Da / Density % sol: 53.56 %
Crystal growTemperature: 289 K / Method: vapor diffusion / Details: 0.1M Bis-Tris buffer pH 5.5 15%(w/v) PEG5000 MME

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Oct 17, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→42.43 Å / Num. obs: 17089 / % possible obs: 94.9 % / Redundancy: 4.9 % / Net I/σ(I): 12.3

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Processing

Software
NameVersionClassification
DENZOdata collection
SCALEPACKdata scaling
MOLREPphasing
CNX2005 parallel (open MP)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1J8F

1j8f


Resolution: 2.3→42.43 Å / Cross valid method: FREE R-VALUE
Details: Authors state that R-work(0.256) is higher than R-free(0.252) due to a rare case
RfactorNum. reflection% reflection
Rfree0.252 --
Rwork0.256 --
obs-17089 94.9 %
Refinement stepCycle: LAST / Resolution: 2.3→42.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2291 0 26 102 2419

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