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- PDB-9s21: Crystal structure of human SIRT2 in complex with SirReal-triazole... -

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Basic information

Entry
Database: PDB / ID: 9s21
TitleCrystal structure of human SIRT2 in complex with SirReal-triazole inhibitor LG023
ComponentsNAD-dependent protein deacetylase sirtuin-2
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
: / (R,R)-2,3-BUTANEDIOL / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 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

Structure viewerMolecule:
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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,0404
Polymers34,4171
Non-polymers6233
Water3,927218
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)35.949, 73.910, 55.495
Angle α, β, γ (deg.)90.00, 95.06, 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: 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-A1JK1 / 2-(4,6-dimethylpyrimidin-2-yl)sulfanyl-~{N}-[5-[[3-(1~{H}-1,2,3-triazol-4-ylmethoxy)phenyl]methyl]-1,3-thiazol-2-yl]ethanamide


Mass: 467.567 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21N7O2S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-BU3 / (R,R)-2,3-BUTANEDIOL


Mass: 90.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 218 / 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: 2.13 Å3/Da / Density % sol: 42.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Crystals of the SIRT2-LG023 complex (11.4 mg/mL SIRT2, 3.33 mM of LG023 with 3.33 % (v/v) final DMSO concentration) formed after one day via microseed matrix screening using crystals from ...Details: Crystals of the SIRT2-LG023 complex (11.4 mg/mL SIRT2, 3.33 mM of LG023 with 3.33 % (v/v) final DMSO concentration) formed after one day via microseed matrix screening using crystals from the SIRT2-Mz242 complex (PDB 8OWZ) in wells with equal volume of protein solution and reservoir solution containing 32% (w/v) PEG MME 2000 in 0.1 M Bis-Tris at pH 6.5.

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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: 1.55→55.28 Å / Num. obs: 38648 / % possible obs: 92.1 % / Redundancy: 6.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.029 / Rrim(I) all: 0.075 / Χ2: 1.06 / Net I/σ(I): 14.5 / Num. measured all: 249168
Reflection shellResolution: 1.55→1.58 Å / % possible obs: 100 % / Redundancy: 6.1 % / Rmerge(I) obs: 0.957 / Num. measured all: 12629 / Num. unique obs: 2069 / CC1/2: 0.675 / Rpim(I) all: 0.421 / Rrim(I) all: 1.048 / Χ2: 1.05 / Net I/σ(I) obs: 2.1

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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: 1.55→44.27 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.61 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2036 1946 5.04 %
Rwork0.1719 --
obs0.1735 38619 92.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.55→44.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2314 0 39 218 2571
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062424
X-RAY DIFFRACTIONf_angle_d0.8373273
X-RAY DIFFRACTIONf_dihedral_angle_d13.37934
X-RAY DIFFRACTIONf_chiral_restr0.05353
X-RAY DIFFRACTIONf_plane_restr0.008428
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.55-1.590.31591460.24932816X-RAY DIFFRACTION100
1.59-1.630.23521490.21762852X-RAY DIFFRACTION100
1.63-1.680.24641580.19942825X-RAY DIFFRACTION100
1.68-1.730.24691170.19292303X-RAY DIFFRACTION81
1.73-1.80.22091330.18212873X-RAY DIFFRACTION100
1.8-1.870.20281600.17052819X-RAY DIFFRACTION100
1.87-1.950.22341120.1711642X-RAY DIFFRACTION59
1.95-2.050.2051450.1632775X-RAY DIFFRACTION99
2.07-2.180.19381350.162397X-RAY DIFFRACTION100
2.18-2.350.19691380.1652564X-RAY DIFFRACTION90
2.35-2.590.19391460.17032852X-RAY DIFFRACTION100
2.59-2.960.20771080.18052652X-RAY DIFFRACTION92
2.97-3.740.20711460.17612530X-RAY DIFFRACTION88
3.74-44.270.18251530.15552773X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: 7.219 Å / Origin y: 17.7249 Å / Origin z: 19.1777 Å
111213212223313233
T0.1371 Å2-0.0039 Å2-0.0071 Å2-0.1668 Å2-0.0013 Å2--0.1672 Å2
L0.32 °2-0.0762 °2-0.1703 °2-0.5655 °2-0.1356 °2--0.9194 °2
S0.0029 Å °0.0706 Å °-0.028 Å °-0.0639 Å °0.0311 Å °0.0421 Å °-0.0152 Å °-0.1468 Å °-0.0389 Å °
Refinement TLS groupSelection details: all

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