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- PDB-5y0z: Human SIRT2 in complex with a specific inhibitor, NPD11033 -

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Basic information

Entry
Database: PDB / ID: 5y0z
TitleHuman SIRT2 in complex with a specific inhibitor, NPD11033
ComponentsNAD-dependent protein deacetylase sirtuin-2
KeywordsHYDROLASE/INHIBITOR / sirtuin / SIRT / NAD-dependent deacetylase / 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 / 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 ...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 / 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 / regulation of phosphorylation / Initiation of Nuclear Envelope (NE) Reformation / protein deacetylation / NAD-dependent histone deacetylase activity / juxtaparanode region of axon / positive regulation of oocyte maturation / protein lysine deacetylase activity / meiotic spindle / response to redox state / regulation of myelination / histone acetyltransferase binding / histone deacetylase activity / 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 / 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 ...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
Chem-8K9 / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsKudo, N. / Ito, A. / Yoshida, M.
Funding support Japan, 2items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science26221204 Japan
Japan Society for the Promotion of Science16K14674 Japan
CitationJournal: Philos. Trans. R. Soc. Lond., B, Biol. Sci. / Year: 2018
Title: Identification of a novel small molecule that inhibits deacetylase but not defatty-acylase reaction catalysed by SIRT2.
Authors: Kudo, N. / Ito, A. / Arata, M. / Nakata, A. / Yoshida, M.
History
DepositionJul 19, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 25, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 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
B: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,4956
Polymers66,4022
Non-polymers1,0924
Water2,594144
1
A: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7473
Polymers33,2011
Non-polymers5462
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7473
Polymers33,2011
Non-polymers5462
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)34.987, 115.685, 71.055
Angle α, β, γ (deg.)90.00, 89.99, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 33201.223 Da / Num. of mol.: 2 / Fragment: UNP residues 52-356 / Mutation: deletion mutation 292-303
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT2, SIR2L, SIR2L2 / Plasmid: pGEX-4T3 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
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.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-8K9 / (1~{R},9~{S})-11-[(2~{R})-3-[2,4-bis(2-methylbutan-2-yl)phenoxy]-2-oxidanyl-propyl]-7,11-diazatricyclo[7.3.1.0^{2,7}]trideca-2,4-dien-6-one


Mass: 480.682 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H44N2O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 144 / 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: 43.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 25%(w/v) PEG 3350, 0.1M BisTris, pH 5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NW12A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Nov 23, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 38772 / % possible obs: 99.9 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.039 / Net I/σ(I): 35.8
Reflection shellResolution: 1.99→2.02 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.075 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0230refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Y6L

4y6l


Resolution: 2→20 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.92 / SU B: 4.714 / SU ML: 0.132 / Cross valid method: THROUGHOUT / ESU R: 0.228 / ESU R Free: 0.18 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.24202 1906 5 %RANDOM
Rwork0.21022 ---
obs0.21184 36188 99.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.401 Å2
Baniso -1Baniso -2Baniso -3
1-2.22 Å20 Å20.3 Å2
2---1.25 Å20 Å2
3----0.97 Å2
Refinement stepCycle: 1 / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4601 0 72 144 4817
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0124785
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0361.666465
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3925573
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.92921.917240
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.15415844
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7161530
X-RAY DIFFRACTIONr_chiral_restr0.0840.2603
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023528
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.2422.7342304
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.0774.0892873
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.4952.922481
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.23636.8767165
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.051 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.292 125 -
Rwork0.227 2674 -
obs--99.54 %

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