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- PDB-5yql: Crystal structure of Sirt2 in complex with selective inhibitor A2I -

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Basic information

Entry
Database: PDB / ID: 5yql
TitleCrystal structure of Sirt2 in complex with selective inhibitor A2I
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 / 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 / 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-A2I / BETA-MERCAPTOETHANOL / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.601 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)35,0515
Polymers34,4501
Non-polymers6014
Water6,882382
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area460 Å2
ΔGint-1 kcal/mol
Surface area14530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.038, 73.950, 55.797
Angle α, β, γ (deg.)90.00, 95.11, 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-A2I / 2-(4,6-dimethylpyrimidin-2-yl)sulfanyl-N-[3-(phenoxymethyl)phenyl]ethanamide


Mass: 379.475 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21N3O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL / 2-Mercaptoethanol


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 382 / 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: 2.15 Å3/Da / Density % sol: 42.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.2M Magnesium Formate, 23-30% (v/v) Polyethylene glycol 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: Feb 24, 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: 37723 / % possible obs: 98.2 % / Redundancy: 3.3 % / Rpim(I) all: 0.07 / Net I/σ(I): 10
Reflection shellHighest resolution: 1.6 Å / CC1/2: 0.791 / Rpim(I) all: 0.276

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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: 1.601→35.895 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.46
RfactorNum. reflection% reflection
Rfree0.1853 1067 2.93 %
Rwork0.1577 --
obs0.1585 36395 94.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.601→35.895 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2343 0 36 382 2761
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062454
X-RAY DIFFRACTIONf_angle_d1.0633305
X-RAY DIFFRACTIONf_dihedral_angle_d14.409918
X-RAY DIFFRACTIONf_chiral_restr0.038354
X-RAY DIFFRACTIONf_plane_restr0.005424
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6005-1.67340.2813990.2333357X-RAY DIFFRACTION72
1.6734-1.76160.23231270.19954314X-RAY DIFFRACTION93
1.7616-1.87190.21331460.17844568X-RAY DIFFRACTION98
1.8719-2.01650.19411180.16234614X-RAY DIFFRACTION99
2.0165-2.21940.17951320.15244594X-RAY DIFFRACTION99
2.2194-2.54040.16151580.14734607X-RAY DIFFRACTION99
2.5404-3.20040.19931490.15334605X-RAY DIFFRACTION99
3.2004-35.90390.16261380.14434669X-RAY DIFFRACTION98

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