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- PDB-5mar: Structure of human SIRT2 in complex with 1,2,4-Oxadiazole inhibit... -

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Basic information

Entry
Database: PDB / ID: 5mar
TitleStructure of human SIRT2 in complex with 1,2,4-Oxadiazole inhibitor and ADP ribose.
ComponentsNAD-dependent protein deacetylase sirtuin-2
KeywordsHYDROLASE / Sirtuin / NAD-dependent Protein deacylase / 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 / NAD-dependent protein lysine deacetylase activity / Schmidt-Lanterman incisure / 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 / 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 / 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 / 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 / midbody / cellular response to oxidative stress / 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 / 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 / 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-7KE / ACETATE ION / Chem-AR6 / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 Å
AuthorsMoniot, S. / Steegborn, C.
Funding support Germany, 1items
OrganizationGrant numberCountry
Alzheimer Forschung Initiative e.V.14834 Germany
CitationJournal: J. Med. Chem. / Year: 2017
Title: Development of 1,2,4-Oxadiazoles as Potent and Selective Inhibitors of the Human Deacetylase Sirtuin 2: Structure-Activity Relationship, X-ray Crystal Structure, and Anticancer Activity.
Authors: Moniot, S. / Forgione, M. / Lucidi, A. / Hailu, G.S. / Nebbioso, A. / Carafa, V. / Baratta, F. / Altucci, L. / Giacche, N. / Passeri, D. / Pellicciari, R. / Mai, A. / Steegborn, C. / Rotili, D.
History
DepositionNov 4, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 15, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2017Group: Database references
Revision 1.2Jan 17, 2024Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_audit_support / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)71,70124
Polymers68,7192
Non-polymers2,98222
Water8,521473
1
A: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,92213
Polymers34,3601
Non-polymers1,56212
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,77911
Polymers34,3601
Non-polymers1,41910
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)76.557, 76.709, 113.827
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 34359.676 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: N-terminal residues HM are cloning artifact / Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT2, SIR2L, SIR2L2 / Plasmid: pET19 modified / Details (production host): His6 SUMO N-terminal fusion tag / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: Q8IXJ6, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides

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Non-polymers , 8 types, 495 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-AR6 / [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE / Adenosine-5-Diphosphoribose


Mass: 559.316 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H23N5O14P2
#4: Chemical ChemComp-7KE / 3-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]propan-1-ol


Mass: 238.670 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H11ClN2O2
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 473 / 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: 2.45 Å3/Da / Density % sol: 49.74 % / Description: bi-pyramidal
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.8
Details: 15-18 % PEG 10,000, 0.1M ammonium acetate, and 0.1M Bis-Tris pH 5.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 19, 2016
RadiationMonochromator: Si-111 crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.89→48.93 Å / Num. obs: 103676 / % possible obs: 100 % / Redundancy: 7.3 % / Biso Wilson estimate: 34.7 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.09 / Net I/σ(I): 14.4
Reflection shellResolution: 1.89→1.93 Å / Redundancy: 7.2 % / Rmerge(I) obs: 0.741 / Mean I/σ(I) obs: 2.5 / CC1/2: 0.56 / % possible all: 100

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Processing

Software
NameClassification
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3zgv

3zgv


Resolution: 1.89→48.93 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.1943 5273 5 %
Rwork0.1732 --
obs-103676 100 %
Displacement parametersBiso mean: 38.23 Å2
Refinement stepCycle: LAST / Resolution: 1.89→48.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4783 0 178 473 5434

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