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- PDB-9s1z: Crystal structure of human SIRT2 in complex with the covalent add... -

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Basic information

Entry
Database: PDB / ID: 9s1z
TitleCrystal structure of human SIRT2 in complex with the covalent adduct of SirReal-triazole inhibitor Mz242 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
: / (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: 1.1 Å
AuthorsFriedrich, F. / Schiedel, M. / 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:
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)35,6404
Polymers34,4171
Non-polymers1,2233
Water6,774376
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)34.827, 72.743, 54.890
Angle α, β, γ (deg.)90.00, 91.31, 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-A1JK7 / [[(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]-3-(2-methoxyethyl)-1$l^{4},2,3-triazacyclopenta-1,4-dien-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate


Mass: 1067.955 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H49N12O16P2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-BU3 / (R,R)-2,3-BUTANEDIOL


Mass: 90.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 376 / 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: 2.02 Å3/Da / Density % sol: 39.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Crystals of the SIRT2-Mz242-ADPR complex (14.0 mg/mL SIRT2, 10 mM NAD+, 0.5 mM Mz242 with 5 % (v/v) final DMSO concentration) formed after three days, with a reservoir solution containing 24 ...Details: Crystals of the SIRT2-Mz242-ADPR complex (14.0 mg/mL SIRT2, 10 mM NAD+, 0.5 mM Mz242 with 5 % (v/v) final DMSO concentration) formed after three days, with a reservoir solution containing 24 % (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: BM07 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 15, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.1→54.88 Å / Num. obs: 108746 / % possible obs: 98.3 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.025 / Rrim(I) all: 0.066 / Χ2: 1.04 / Net I/σ(I): 14 / Num. measured all: 725487
Reflection shellResolution: 1.1→1.12 Å / % possible obs: 97.4 % / Redundancy: 6.6 % / Rmerge(I) obs: 1.226 / Num. measured all: 35371 / Num. unique obs: 5347 / CC1/2: 0.716 / Rpim(I) all: 0.508 / Rrim(I) all: 1.329 / Χ2: 1 / Net I/σ(I) obs: 1.6

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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: 1.1→23.01 Å / SU ML: 0.11 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.18 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1769 5517 5.08 %
Rwork0.1653 --
obs0.1659 108693 98.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.1→23.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2347 0 78 376 2801
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112518
X-RAY DIFFRACTIONf_angle_d1.1373417
X-RAY DIFFRACTIONf_dihedral_angle_d12.72991
X-RAY DIFFRACTIONf_chiral_restr0.076368
X-RAY DIFFRACTIONf_plane_restr0.011448
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.1-1.110.34141910.28913404X-RAY DIFFRACTION98
1.11-1.130.29541660.27733452X-RAY DIFFRACTION97
1.13-1.140.26951810.26733370X-RAY DIFFRACTION97
1.14-1.150.26251850.25823419X-RAY DIFFRACTION98
1.15-1.170.27912240.24933421X-RAY DIFFRACTION98
1.17-1.180.24631650.25993287X-RAY DIFFRACTION96
1.18-1.20.25891940.23953446X-RAY DIFFRACTION98
1.2-1.220.23031690.22053426X-RAY DIFFRACTION98
1.22-1.240.22542020.2233438X-RAY DIFFRACTION98
1.24-1.260.22481920.21563417X-RAY DIFFRACTION98
1.26-1.280.24291860.21153438X-RAY DIFFRACTION99
1.28-1.30.22691630.20853466X-RAY DIFFRACTION99
1.3-1.330.21441710.20463418X-RAY DIFFRACTION98
1.33-1.360.22311530.19253361X-RAY DIFFRACTION96
1.36-1.390.20431660.19363480X-RAY DIFFRACTION99
1.39-1.420.18961900.18833430X-RAY DIFFRACTION99
1.42-1.450.1872070.17423462X-RAY DIFFRACTION99
1.45-1.490.18311850.1723442X-RAY DIFFRACTION99
1.49-1.540.16352050.1633433X-RAY DIFFRACTION99
1.54-1.590.18472090.15593439X-RAY DIFFRACTION99
1.59-1.640.18611630.16153430X-RAY DIFFRACTION98
1.64-1.710.16421950.15773414X-RAY DIFFRACTION98
1.71-1.790.14451990.15263487X-RAY DIFFRACTION99
1.79-1.880.16151910.14923450X-RAY DIFFRACTION99
1.88-20.17321840.1523467X-RAY DIFFRACTION99
2-2.150.16731850.14553479X-RAY DIFFRACTION99
2.15-2.370.15971640.14483442X-RAY DIFFRACTION97
2.37-2.710.16361560.15233540X-RAY DIFFRACTION100
2.71-3.410.16681770.14993516X-RAY DIFFRACTION99
3.41-23.010.14731990.14563502X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: 8.9327 Å / Origin y: 15.1531 Å / Origin z: 9.0321 Å
111213212223313233
T0.078 Å20.0048 Å2-0.0044 Å2-0.0827 Å20.0073 Å2--0.1005 Å2
L0.4029 °20.1018 °20.0222 °2-0.7353 °20.1904 °2--0.8639 °2
S0.0142 Å °-0.0625 Å °-0.0337 Å °0.0314 Å °0.0136 Å °-0.0111 Å °0.0234 Å °0.0401 Å °-0.0273 Å °
Refinement TLS groupSelection details: all

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