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- PDB-8py3: Crystal structure of human Sirt2 in complex with a 1,2,4-oxadiazo... -

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Basic information

Entry
Database: PDB / ID: 8py3
TitleCrystal structure of human Sirt2 in complex with a 1,2,4-oxadiazole based inhibitor
ComponentsNAD-dependent protein deacetylase sirtuin-2
KeywordsHYDROLASE / Inhibitor / Sirtuin 2
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 / epigenetic regulation of gene expression / heterochromatin formation / 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 / cytoplasm / cytosol
Similarity search - Function
Sirtuin, class I / Sirtuin, catalytic core small domain superfamily / Sirtuin family / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / DHS-like NAD/FAD-binding domain superfamily
Similarity search - Domain/homology
: / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsFriedrich, F. / Colcerasa, A. / Einsle, O. / Jung, M.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Research Foundation (DFG)SFB 992 Germany
German Research Foundation (DFG)295/18-1 Germany
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Activity Studies of 1,2,4-Oxadiazoles for the Inhibition of the NAD + -Dependent Lysine Deacylase Sirtuin 2.
Authors: Colcerasa, A. / Friedrich, F. / Melesina, J. / Moser, P. / Vogelmann, A. / Tzortzoglou, P. / Neuwirt, E. / Sum, M. / Robaa, D. / Zhang, L. / Ramos-Morales, E. / Romier, C. / Einsle, O. / ...Authors: Colcerasa, A. / Friedrich, F. / Melesina, J. / Moser, P. / Vogelmann, A. / Tzortzoglou, P. / Neuwirt, E. / Sum, M. / Robaa, D. / Zhang, L. / Ramos-Morales, E. / Romier, C. / Einsle, O. / Metzger, E. / Schule, R. / Gross, O. / Sippl, W. / Jung, M.
History
DepositionJul 24, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)35,5219
Polymers34,4171
Non-polymers1,1048
Water3,801211
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.123, 73.430, 55.038
Angle α, β, γ (deg.)90.00, 95.64, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 34416.727 Da / Num. of mol.: 1 / Fragment: UNP residues 56-356
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

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Non-polymers , 5 types, 219 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-I1R / 4-chloranyl-~{N}-[4-[5-[[(3~{S})-1-[(3-fluoranyl-2-methyl-phenyl)methyl]piperidin-3-yl]methyl]-1,2,4-oxadiazol-3-yl]phenyl]benzamide


Mass: 519.010 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C29H28ClFN4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER


Mass: 209.240 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 43.38 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 25 % PEG 3,350, 0.22 M Bis-Tris pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Jun 22, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.65→54.77 Å / Num. obs: 34038 / % possible obs: 98.8 % / Redundancy: 7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.032 / Rrim(I) all: 0.084 / Χ2: 1.06 / Net I/σ(I): 13.4
Reflection shellResolution: 1.65→1.68 Å / % possible obs: 99.1 % / Redundancy: 7.3 % / Rmerge(I) obs: 0.792 / Num. measured all: 12249 / Num. unique obs: 1688 / CC1/2: 0.847 / Rpim(I) all: 0.313 / Rrim(I) all: 0.852 / Χ2: 1.04 / Net I/σ(I) obs: 2.5

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→54.77 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1849 1711 5.03 %
Rwork0.1659 --
obs0.1669 34010 98.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.65→54.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2347 0 72 211 2630
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072510
X-RAY DIFFRACTIONf_angle_d0.993386
X-RAY DIFFRACTIONf_dihedral_angle_d6.759382
X-RAY DIFFRACTIONf_chiral_restr0.057360
X-RAY DIFFRACTIONf_plane_restr0.011443
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.70.28131230.21992733X-RAY DIFFRACTION99
1.7-1.750.22451570.2012626X-RAY DIFFRACTION99
1.75-1.820.23651560.21232698X-RAY DIFFRACTION99
1.82-1.890.24831570.19642672X-RAY DIFFRACTION99
1.89-1.970.21331250.17782719X-RAY DIFFRACTION99
1.97-2.080.20291410.16842684X-RAY DIFFRACTION99
2.08-2.210.17951520.17422691X-RAY DIFFRACTION99
2.21-2.380.22171380.16892539X-RAY DIFFRACTION93
2.38-2.620.19551440.17462684X-RAY DIFFRACTION98
2.62-30.2011540.17092715X-RAY DIFFRACTION100
3-3.780.16291400.15562729X-RAY DIFFRACTION100
3.78-54.770.1371240.14322809X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 6.8139 Å / Origin y: 17.4952 Å / Origin z: 18.5877 Å
111213212223313233
T0.1198 Å2-0.0006 Å2-0.009 Å2-0.1582 Å2-0.0029 Å2--0.1595 Å2
L0.4168 °2-0.1825 °2-0.145 °2-0.5916 °2-0.0201 °2--0.6783 °2
S0.0208 Å °0.0532 Å °-0.0417 Å °-0.0287 Å °0.0143 Å °0.0565 Å °-0.0358 Å °-0.1664 Å °-0 Å °
Refinement TLS groupSelection details: all

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