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- PDB-9s22: Crystal structure of human SIRT2 in complex with the covalent add... -

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Basic information

Entry
Database: PDB / ID: 9s22
TitleCrystal structure of human SIRT2 in complex with the covalent adduct of SirReal-triazole inhibitor LG023 and ADP-ribose
ComponentsNAD-dependent protein deacetylase sirtuin-2
KeywordsHYDROLASE / Sirtuins / Inhibitor / Covalent adduct / 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: 1.95 Å
AuthorsFriedrich, F. / Gaitzsch, L. / Einsle, O. / 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

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4913
Polymers34,4171
Non-polymers1,0742
Water2,270126
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14090 Å2
Unit cell
Length a, b, c (Å)102.614, 47.457, 74.795
Angle α, β, γ (deg.)90.00, 108.00, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-547-

HOH

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Components

#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: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-A1JK2 / [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{S})-5-[5-[[3-[[2-[2-(4,6-dimethylpyrimidin-2-yl)sulfanylethanoylamino]-1,3-thiazol-5-yl]methyl]phenoxy]methyl]-1,2,3-triazol-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate


Mass: 1008.868 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H42N12O15P2S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 126 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.52 Å3/Da / Density % sol: 51.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Crystals of the SIRT2-[LG023-ADPR] complex (11.4 mg/mL SIRT2, 10 mM NAD+, 3.33 mM of compound LG023 with 3.33 % (v/v) final DMSO concentration) formed after three days, with a reservoir ...Details: Crystals of the SIRT2-[LG023-ADPR] complex (11.4 mg/mL SIRT2, 10 mM NAD+, 3.33 mM of compound LG023 with 3.33 % (v/v) final DMSO concentration) formed after three days, with a reservoir solution containing 25 % (w/v) PEG 3350 and 0.2 M MgCl2 x 6H2O in 0.1 M Tris at pH 8.5.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.8731 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Mar 9, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 1.95→71.14 Å / Num. obs: 23415 / % possible obs: 93 % / Redundancy: 3.3 % / CC1/2: 0.997 / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.054 / Rrim(I) all: 0.1 / Χ2: 1.04 / Net I/σ(I): 8.5 / Num. measured all: 77177
Reflection shellResolution: 1.95→2 Å / % possible obs: 99.7 % / Redundancy: 3.4 % / Rmerge(I) obs: 1.161 / Num. measured all: 5949 / Num. unique obs: 1740 / CC1/2: 0.511 / Rpim(I) all: 0.733 / Rrim(I) all: 1.377 / Χ2: 1.07 / Net I/σ(I) obs: 1.1

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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: 1.95→71.14 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2143 1157 4.95 %
Rwork0.1779 --
obs0.1797 23390 92.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.95→71.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2383 0 68 126 2577
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092539
X-RAY DIFFRACTIONf_angle_d1.0473445
X-RAY DIFFRACTIONf_dihedral_angle_d5.833399
X-RAY DIFFRACTIONf_chiral_restr0.057371
X-RAY DIFFRACTIONf_plane_restr0.01451
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-2.040.3491440.32022951X-RAY DIFFRACTION100
2.04-2.150.3341270.24972469X-RAY DIFFRACTION83
2.15-2.280.26561730.2352638X-RAY DIFFRACTION89
2.28-2.460.26341560.20732959X-RAY DIFFRACTION100
2.46-2.70.28561250.19252620X-RAY DIFFRACTION88
2.7-3.10.22241460.18512996X-RAY DIFFRACTION100
3.1-3.870.17511230.15682655X-RAY DIFFRACTION91
3.91-71.140.1731630.14532945X-RAY DIFFRACTION97
Refinement TLS params.Method: refined / Origin x: -7.8613 Å / Origin y: -7.0585 Å / Origin z: 16.1017 Å
111213212223313233
T0.2094 Å20.0083 Å2-0.0101 Å2-0.2322 Å20.0142 Å2--0.2066 Å2
L1.7037 °20.615 °20.3794 °2-1.3793 °20.3821 °2--1.5044 °2
S0.0695 Å °-0.272 Å °-0.0343 Å °-0.0602 Å °-0.0927 Å °-0.0008 Å °0.0582 Å °-0.1306 Å °0.0151 Å °
Refinement TLS groupSelection details: all

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