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- PDB-9s27: Crystal structure of human SIRT3 in complex with the covalent add... -

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Basic information

Entry
Database: PDB / ID: 9s27
TitleCrystal structure of human SIRT3 in complex with the covalent adduct of peptide triazole inhibitor LTDi1 and ADP-ribose
Components
  • NAD-dependent protein deacetylase sirtuin-3, mitochondrial
  • TNFa-derived lysine triazole dodecyl inhibitor
KeywordsHYDROLASE / Sirtuins / Mechanistic Inhibitor / Deacetylation / Covalent adduct
Function / homology
Function and homology information


positive regulation of superoxide dismutase activity / positive regulation of catalase activity / NAD-dependent protein lysine delactylase activity / positive regulation of ceramide biosynthetic process / Maturation of TCA enzymes and regulation of TCA cycle / peptidyl-lysine deacetylation / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / protein deacetylation / histone deacetylase activity, NAD-dependent ...positive regulation of superoxide dismutase activity / positive regulation of catalase activity / NAD-dependent protein lysine delactylase activity / positive regulation of ceramide biosynthetic process / Maturation of TCA enzymes and regulation of TCA cycle / peptidyl-lysine deacetylation / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / protein deacetylation / histone deacetylase activity, NAD-dependent / positive regulation of oxidative phosphorylation / Regulation of FOXO transcriptional activity by acetylation / protein lysine deacetylase activity / cellular response to stress / negative regulation of reactive oxygen species metabolic process / NAD+ binding / Mitochondrial unfolded protein response (UPRmt) / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / aerobic respiration / Transcriptional activation of mitochondrial biogenesis / positive regulation of insulin secretion / negative regulation of ERK1 and ERK2 cascade / sequence-specific DNA binding / mitochondrial matrix / enzyme binding / protein-containing complex / mitochondrion / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
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-3, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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

Downloads & links

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-3, mitochondrial
B: TNFa-derived lysine triazole dodecyl inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1796
Polymers32,1122
Non-polymers1,0674
Water4,107228
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2920 Å2
ΔGint-4 kcal/mol
Surface area12650 Å2
Unit cell
Length a, b, c (Å)97.102, 97.102, 203.673
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11A-623-

HOH

21A-650-

HOH

31A-662-

HOH

41A-719-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein NAD-dependent protein deacetylase sirtuin-3, mitochondrial / hSIRT3 / Regulatory protein SIR2 homolog 3 / SIR2-like protein 3


Mass: 31268.049 Da / Num. of mol.: 1 / Fragment: UNP residues 118-395
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT3, SIR2L3 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9NTG7, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Protein/peptide TNFa-derived lysine 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, 232 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-BU3 / (R,R)-2,3-BUTANEDIOL


Mass: 90.121 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O2
#5: Chemical ChemComp-A1JK8 / [[(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-dodecyl-3-propyl-1,2,3$l^{4}-triazacyclopenta-2,4-dien-1-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate


Mass: 821.772 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H55N8O13P2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 228 / 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: 2.84 Å3/Da / Density % sol: 56.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Crystals of the SIRT3-[LTDi1-ADPR] complex (10.0 mg/mL SIRT3, 15 mM NAD+, 3 mM of LTDi1 with 1.5 % (v/v) final DMSO concentration) formed after 2 days in wells with an equal volume of 300 nL ...Details: Crystals of the SIRT3-[LTDi1-ADPR] complex (10.0 mg/mL SIRT3, 15 mM NAD+, 3 mM of LTDi1 with 1.5 % (v/v) final DMSO concentration) formed after 2 days in wells with an equal volume of 300 nL protein solution and 300 nL reservoir solution containing 3 M NaCl 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: ID23-2 / Wavelength: 0.8731 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Feb 12, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 1.6→77.73 Å / Num. obs: 48997 / % possible obs: 100 % / Redundancy: 17.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.17 / Rpim(I) all: 0.041 / Rrim(I) all: 0.175 / Χ2: 0.99 / Net I/σ(I): 14.5 / Num. measured all: 876921
Reflection shellResolution: 1.6→1.63 Å / % possible obs: 100 % / Redundancy: 17.5 % / Rmerge(I) obs: 3.074 / Num. measured all: 41732 / Num. unique obs: 2380 / CC1/2: 0.295 / Rpim(I) all: 0.75 / Rrim(I) all: 3.165 / Χ2: 0.97 / 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: 1.6→77.73 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21.76 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1938 2444 4.99 %
Rwork0.1807 --
obs0.1814 48988 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.6→77.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2236 0 13 228 2477
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072350
X-RAY DIFFRACTIONf_angle_d0.9083216
X-RAY DIFFRACTIONf_dihedral_angle_d12.233910
X-RAY DIFFRACTIONf_chiral_restr0.057369
X-RAY DIFFRACTIONf_plane_restr0.009417
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.630.33521580.32722678X-RAY DIFFRACTION100
1.63-1.670.37171360.31312721X-RAY DIFFRACTION100
1.67-1.710.34831440.30362681X-RAY DIFFRACTION100
1.71-1.750.27691490.27942719X-RAY DIFFRACTION100
1.75-1.80.32221350.27612730X-RAY DIFFRACTION100
1.8-1.850.27111300.25452698X-RAY DIFFRACTION100
1.85-1.910.23571510.21272731X-RAY DIFFRACTION100
1.91-1.980.21891360.18582710X-RAY DIFFRACTION100
1.98-2.060.22211460.16842730X-RAY DIFFRACTION100
2.06-2.150.18871330.17142747X-RAY DIFFRACTION100
2.15-2.260.22321300.17772746X-RAY DIFFRACTION100
2.26-2.410.18581340.16152720X-RAY DIFFRACTION100
2.41-2.590.19731500.16782753X-RAY DIFFRACTION100
2.59-2.850.2051460.17782757X-RAY DIFFRACTION100
2.85-3.260.18261410.17092762X-RAY DIFFRACTION100
3.27-4.110.14051690.14042764X-RAY DIFFRACTION100
4.11-77.730.15631560.16312897X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -15.5677 Å / Origin y: 39.5647 Å / Origin z: 17.7436 Å
111213212223313233
T0.1584 Å2-0.0223 Å2-0.0371 Å2-0.1306 Å2-0.0042 Å2--0.1466 Å2
L1.1909 °2-0.314 °2-0.3679 °2-0.803 °20.5322 °2--1.569 °2
S-0.0202 Å °0.0381 Å °-0.0482 Å °-0.0053 Å °-0.0368 Å °0.0809 Å °0.08 Å °-0.0932 Å °0.0569 Å °
Refinement TLS groupSelection details: all

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