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- PDB-5yqn: Crystal structure of Sirt2 in complex with selective inhibitor L55 -

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Basic information

Entry
Database: PDB / ID: 5yqn
TitleCrystal structure of Sirt2 in complex with selective inhibitor L55
ComponentsNAD-dependent protein deacetylase sirtuin-2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / NAD-dependent deacetylase sirtuin-2 / Inhibitor / Complex / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / negative regulation of striated muscle tissue development / negative regulation of satellite cell differentiation / histone H4K16 deacetylase activity, NAD-dependent / positive regulation of attachment of spindle microtubules to kinetochore / positive regulation of meiotic nuclear division / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / paranodal junction ...cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / negative regulation of striated muscle tissue development / negative regulation of satellite cell differentiation / histone H4K16 deacetylase activity, NAD-dependent / positive regulation of attachment of spindle microtubules to kinetochore / positive regulation of meiotic nuclear division / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / paranodal junction / peptidyl-lysine deacetylation / tubulin deacetylation / lateral loop / NLRP3 inflammasome complex assembly / negative regulation of NLRP3 inflammasome complex assembly / mitotic nuclear membrane reassembly / tubulin deacetylase activity / paranode region of axon / regulation of exit from mitosis / positive regulation of fatty acid biosynthetic process / Schmidt-Lanterman incisure / negative regulation of peptidyl-threonine phosphorylation / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / regulation of phosphorylation / myelination in peripheral nervous system / rDNA heterochromatin formation / protein deacetylation / histone deacetylase activity, NAD-dependent / positive regulation of oocyte maturation / juxtaparanode region of axon / Initiation of Nuclear Envelope (NE) Reformation / chromatin silencing complex / meiotic spindle / protein lysine deacetylase activity / response to redox state / regulation of myelination / positive regulation of DNA binding / histone deacetylase activity / negative regulation of fat cell differentiation / histone acetyltransferase binding / negative regulation of reactive oxygen species metabolic process / positive regulation of cell division / NAD+ poly-ADP-ribosyltransferase activity / NAD+ binding / positive regulation of execution phase of apoptosis / glial cell projection / subtelomeric heterochromatin formation / heterochromatin / lipid catabolic process / cellular response to epinephrine stimulus / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / centriole / substantia nigra development / negative regulation of autophagy / epigenetic regulation of gene expression / ubiquitin binding / meiotic cell cycle / negative regulation of protein catabolic process / autophagy / spindle / histone deacetylase binding / mitotic spindle / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / heterochromatin formation / myelin sheath / chromosome / growth cone / cellular response to oxidative stress / midbody / perikaryon / cellular response to hypoxia / DNA-binding transcription factor binding / proteasome-mediated ubiquitin-dependent protein catabolic process / microtubule / chromosome, telomeric region / regulation of cell cycle / innate immune response / cell division / 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 / cytoplasm / cytosol
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
Chem-L55 / DI(HYDROXYETHYL)ETHER / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsWang, H. / Yu, Y. / Li, G. / Chen, Q.
CitationJournal: Eur J Med Chem / Year: 2018
Title: X-ray crystal structure guided discovery of new selective, substrate-mimicking sirtuin 2 inhibitors that exhibit activities against non-small cell lung cancer cells.
Authors: Yang, L.L. / Wang, H.L. / Zhong, L. / Yuan, C. / Liu, S.Y. / Yu, Z.J. / Liu, S. / Yan, Y.H. / Wu, C. / Wang, Y. / Wang, Z. / Yu, Y. / Chen, Q. / Li, G.B.
History
DepositionNov 7, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 17, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1244
Polymers34,4501
Non-polymers6743
Water5,332296
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint3 kcal/mol
Surface area13900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)35.864, 73.510, 55.573
Angle α, β, γ (deg.)90.00, 95.18, 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: 34449.668 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-L55 / N-[3-[[3-[2-(4,6-dimethylpyrimidin-2-yl)sulfanylethanoylamino]phenyl]methoxy]phenyl]-1-methyl-pyrazole-4-carboxamide


Mass: 502.588 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H26N6O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 296 / 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: 2.12 Å3/Da / Density % sol: 41.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1M HEPES PH7.4, 30% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 37688 / % possible obs: 99.5 % / Redundancy: 3.4 % / Rpim(I) all: 0.07 / Net I/σ(I): 10
Reflection shellCC1/2: 0.859 / Rpim(I) all: 0.223

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MAT

5mat


Resolution: 1.6→32.126 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 19.7
RfactorNum. reflection% reflection
Rfree0.2038 1855 4.97 %
Rwork0.1735 --
obs0.175 37339 98.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.6→32.126 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2274 0 44 296 2614
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062398
X-RAY DIFFRACTIONf_angle_d1.0863235
X-RAY DIFFRACTIONf_dihedral_angle_d14.296895
X-RAY DIFFRACTIONf_chiral_restr0.038346
X-RAY DIFFRACTIONf_plane_restr0.005415
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.64320.25891250.20852537X-RAY DIFFRACTION92
1.6432-1.69160.21581340.20122670X-RAY DIFFRACTION97
1.6916-1.74620.23461380.19742710X-RAY DIFFRACTION98
1.7462-1.80860.19751630.18932728X-RAY DIFFRACTION98
1.8086-1.8810.21391200.18442737X-RAY DIFFRACTION99
1.881-1.96660.21921430.17692757X-RAY DIFFRACTION100
1.9666-2.07030.21691350.17262737X-RAY DIFFRACTION100
2.0703-2.20.18351550.17242735X-RAY DIFFRACTION99
2.2-2.36980.19061600.16052750X-RAY DIFFRACTION99
2.3698-2.60810.2041460.17112745X-RAY DIFFRACTION99
2.6081-2.98530.19671540.17012781X-RAY DIFFRACTION100
2.9853-3.76030.22091500.16442759X-RAY DIFFRACTION100
3.7603-32.13250.18531320.172838X-RAY DIFFRACTION99

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