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- PDB-9s23: Crystal structure of human SIRT2 in complex with peptide triazole... -

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Basic information

Entry
Database: PDB / ID: 9s23
TitleCrystal structure of human SIRT2 in complex with peptide triazole inhibitor OTDi1
Components
  • NAD-dependent protein deacetylase sirtuin-2
  • TNFa-derived ornithine triazole dodecyl inhibitor
KeywordsHYDROLASE / Sirtuins / Inhibitor / Deacetylation
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 / tubulin deacetylation / peptidyl-lysine 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 / Schmidt-Lanterman incisure / positive regulation of fatty acid biosynthetic process / negative regulation of peptidyl-threonine phosphorylation / NAD-dependent protein lysine deacetylase activity / regulation of phosphorylation / protein acetyllysine N-acetyltransferase / 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 / histone acetyltransferase binding / negative regulation of fat cell differentiation / negative regulation of reactive oxygen species metabolic process / positive regulation of cell division / NAD+ poly-ADP-ribosyltransferase activity / NAD+ binding / glial cell projection / positive regulation of execution phase of apoptosis / subtelomeric heterochromatin formation / heterochromatin / lipid catabolic process / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / cellular response to epinephrine stimulus / 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 / 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: 2.3 Å
AuthorsFriedrich, F. / Meleshin, M. / Einsle, O. / Schutkowski, M. / Jung, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)Ju295/18-1 Germany
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2025
Title: From Pharmacophore to Warhead: NAD + -Targeting Triazoles as Mechanism-Based Sirtuin Inhibitors.
Authors: Friedrich, F. / Meleshin, M. / Papenkordt, N. / Gaitzsch, L. / Prucker, I. / Borso, M. / Ruprecht, J. / Vorreiter, C. / Rast, S. / Zhang, L. / Schiedel, M. / Sippl, W. / Imhof, A. / Jessen, ...Authors: Friedrich, F. / Meleshin, M. / Papenkordt, N. / Gaitzsch, L. / Prucker, I. / Borso, M. / Ruprecht, J. / Vorreiter, C. / Rast, S. / Zhang, L. / Schiedel, M. / Sippl, W. / Imhof, A. / Jessen, H.J. / Einsle, O. / Schutkowski, M. / Jung, M.
History
DepositionJul 21, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-2
C: TNFa-derived ornithine triazole dodecyl inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6545
Polymers35,2612
Non-polymers3933
Water61334
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1750 Å2
ΔGint-5 kcal/mol
Surface area13460 Å2
Unit cell
Length a, b, c (Å)89.621, 89.621, 133.033
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-523-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AC

#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
#2: Protein/peptide TNFa-derived ornithine triazole dodecyl inhibitor


Mass: 843.944 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Non-polymers , 4 types, 37 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-A1JK5 / 4-dodecyl-1-ethyl-1,2,3-triazole


Mass: 265.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H31N3 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 34 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 3.75 Å3/Da / Density % sol: 67.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Crystals of the SIRT2-OTDi1 complex (11.0 mg/mL SIRT2, 5 mM of OTDi1 with 2.5 % (v/v) final DMSO concentration) formed after one day in wells with an equal volume of protein solution and ...Details: Crystals of the SIRT2-OTDi1 complex (11.0 mg/mL SIRT2, 5 mM of OTDi1 with 2.5 % (v/v) final DMSO concentration) formed after one day in wells with an equal volume of protein solution and reservoir solution containing 21.5 % (w/v) PEG 3350 in 0.1 M Bis-Tris at pH 6.7.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8731 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 6, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 2.3→74.33 Å / Num. obs: 24808 / % possible obs: 100 % / Redundancy: 26.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.352 / Rpim(I) all: 0.069 / Rrim(I) all: 0.358 / Χ2: 1.02 / Net I/σ(I): 12.5 / Num. measured all: 658807
Reflection shellResolution: 2.3→2.38 Å / % possible obs: 100 % / Redundancy: 27.2 % / Rmerge(I) obs: 3.592 / Num. measured all: 64498 / Num. unique obs: 2368 / CC1/2: 0.335 / Rpim(I) all: 0.693 / Rrim(I) all: 3.659 / Χ2: 1.02 / Net I/σ(I) obs: 1.3

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
Aimlessdata scaling
autoPROCdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→53.41 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.259 1227 4.96 %
Rwork0.2262 --
obs0.2278 24723 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3→53.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2280 0 5 34 2319
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022342
X-RAY DIFFRACTIONf_angle_d0.5413154
X-RAY DIFFRACTIONf_dihedral_angle_d13.106894
X-RAY DIFFRACTIONf_chiral_restr0.039343
X-RAY DIFFRACTIONf_plane_restr0.004402
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.390.37241360.34872537X-RAY DIFFRACTION100
2.39-2.50.32811360.3392555X-RAY DIFFRACTION100
2.5-2.630.3191510.30752557X-RAY DIFFRACTION100
2.63-2.80.28011290.27042568X-RAY DIFFRACTION100
2.8-3.010.30071330.25782602X-RAY DIFFRACTION100
3.01-3.320.23351340.2342580X-RAY DIFFRACTION100
3.32-3.80.2261360.20572620X-RAY DIFFRACTION100
3.8-4.780.18721260.17632668X-RAY DIFFRACTION100
4.78-53.410.28291460.20252809X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -28.4903 Å / Origin y: -5.878 Å / Origin z: -24.7634 Å
111213212223313233
T0.3489 Å2-0.0408 Å20.0444 Å2-0.3004 Å20.0055 Å2--0.2376 Å2
L1.7421 °2-1.1105 °20.8472 °2-4.9624 °2-1.9622 °2--2.3225 °2
S-0.0404 Å °0.1659 Å °-0.0513 Å °-0.3244 Å °-0.1562 Å °-0.3203 Å °0.3185 Å °0.0696 Å °0.1475 Å °
Refinement TLS groupSelection details: all

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