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- PDB-8v15: Human SIRT3 bound to p53-AMC peptide, Carba-NAD, and Honokiol -

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Basic information

Entry
Database: PDB / ID: 8v15
TitleHuman SIRT3 bound to p53-AMC peptide, Carba-NAD, and Honokiol
Components
  • GLN-PRO-LYS-FDL
  • NAD-dependent protein deacetylase sirtuin-3, mitochondrial
KeywordsHYDROLASE / Activator / Complex / Deacylase
Function / homology
Function and homology information


positive regulation of catalase activity / positive regulation of ceramide biosynthetic process / peptidyl-lysine deacetylation / positive regulation of superoxide dismutase activity / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / NAD-dependent histone deacetylase activity / protein deacetylation / Regulation of FOXO transcriptional activity by acetylation / NAD+ binding ...positive regulation of catalase activity / positive regulation of ceramide biosynthetic process / peptidyl-lysine deacetylation / positive regulation of superoxide dismutase activity / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / NAD-dependent histone deacetylase activity / protein deacetylation / Regulation of FOXO transcriptional activity by acetylation / NAD+ binding / negative regulation of reactive oxygen species metabolic process / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / aerobic respiration / Transcriptional activation of mitochondrial biogenesis / negative regulation of ERK1 and ERK2 cascade / positive regulation of insulin secretion / transferase activity / 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
CARBA-NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Chem-Y4T / NAD-dependent protein deacetylase sirtuin-3, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsChakrabarti, R. / Ghosh, A. / Guan, X. / Upadhyay, A. / Dumpati, R.K. / Munshi, S. / Roy, S. / Chall, S. / Rahnamoun, A. / Reverdy, C. ...Chakrabarti, R. / Ghosh, A. / Guan, X. / Upadhyay, A. / Dumpati, R.K. / Munshi, S. / Roy, S. / Chall, S. / Rahnamoun, A. / Reverdy, C. / Errasti, G. / Delacroix, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: biorxiv / Year: 2023
Title: Computationally Driven Discovery and Characterization of SIRT3 Activating Compounds that Fully Recover Catalytic Activity under NAD+ Depletion
Authors: Chakrabarti, R. / Ghosh, A. / Guan, X. / Upadhyay, A. / Dumpati, R.K. / Munshi, S. / Roy, S. / Chall, S. / Rahnamoun, A. / Reverdy, C. / Errasti, G. / Delacroix, T.
History
DepositionNov 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2023Provider: 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: GLN-PRO-LYS-FDL
C: NAD-dependent protein deacetylase sirtuin-3, mitochondrial
D: GLN-PRO-LYS-FDL
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,8029
Polymers64,0804
Non-polymers1,7225
Water55831
1
A: NAD-dependent protein deacetylase sirtuin-3, mitochondrial
B: GLN-PRO-LYS-FDL
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7684
Polymers32,0402
Non-polymers7282
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2070 Å2
ΔGint-12 kcal/mol
Surface area12260 Å2
MethodPISA
2
C: NAD-dependent protein deacetylase sirtuin-3, mitochondrial
D: GLN-PRO-LYS-FDL
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0345
Polymers32,0402
Non-polymers9943
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2200 Å2
ΔGint-12 kcal/mol
Surface area12090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)34.683, 159.432, 53.047
Angle α, β, γ (deg.)90.00, 90.61, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ACBD

#1: Protein NAD-dependent protein deacetylase sirtuin-3, mitochondrial


Mass: 31340.084 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT3
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q9NTG7
#2: Protein/peptide GLN-PRO-LYS-FDL


Mass: 699.816 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: Residues 317-320 of acetylated p53 -- QPK(KAc) -- linked to 7-amino-4-methylcoumarin
Source: (synth.) Homo sapiens (human)

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Non-polymers , 4 types, 36 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-CNA / CARBA-NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 662.460 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H30N7O13P2
#5: Chemical ChemComp-Y4T / (1P)-3',5-di(prop-2-en-1-yl)[1,1'-biphenyl]-2,4'-diol / Honokiol


Mass: 266.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.41 Å3/Da / Density % sol: 48.96 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion
Details: SIRT3 (118-399) (10.3 mg/ml) was crystallized in complex with FDL (QPKKAC-7-amino-4-methylcoumarin) peptide (3 mM) and honokiol (1 mM) in 25% PEG 3350, 0.2 M Li2SO4 (or 0.2 M NaCl), and 0.1M ...Details: SIRT3 (118-399) (10.3 mg/ml) was crystallized in complex with FDL (QPKKAC-7-amino-4-methylcoumarin) peptide (3 mM) and honokiol (1 mM) in 25% PEG 3350, 0.2 M Li2SO4 (or 0.2 M NaCl), and 0.1M HEPES, pH 7.5 as reservoir. Following formation of the ternary complex, crystals were soaked with carba-NAD (10 mM).

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.9786 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 2, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.4→44.16 Å / Num. obs: 21620 / % possible obs: 96.2 % / Redundancy: 3.1 % / CC1/2: 0.983 / Net I/σ(I): 10.4
Reflection shellResolution: 2.4→2.44 Å / Num. unique obs: 964 / CC1/2: 0.807

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→44.16 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.891 / SU B: 13.322 / SU ML: 0.301 / Cross valid method: THROUGHOUT / ESU R: 0.608 / ESU R Free: 0.348 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.30262 1038 4.8 %RANDOM
Rwork0.19442 ---
obs0.19947 20550 95.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 56.789 Å2
Baniso -1Baniso -2Baniso -3
1-0.43 Å2-0 Å20.12 Å2
2---0.15 Å2-0 Å2
3----0.29 Å2
Refinement stepCycle: 1 / Resolution: 2.4→44.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4286 0 110 31 4427
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0124529
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164301
X-RAY DIFFRACTIONr_angle_refined_deg2.9141.8446194
X-RAY DIFFRACTIONr_angle_other_deg0.9571.7319891
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.7795547
X-RAY DIFFRACTIONr_dihedral_angle_2_deg22.0725.34943
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.94310685
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.1310.2707
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.025235
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021017
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it9.9385.4952194
X-RAY DIFFRACTIONr_mcbond_other9.9395.4942191
X-RAY DIFFRACTIONr_mcangle_it12.8329.8322730
X-RAY DIFFRACTIONr_mcangle_other12.8339.8312729
X-RAY DIFFRACTIONr_scbond_it11.3186.2872335
X-RAY DIFFRACTIONr_scbond_other11.3166.2882336
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other15.75411.2753462
X-RAY DIFFRACTIONr_long_range_B_refined18.66160.345350
X-RAY DIFFRACTIONr_long_range_B_other18.66360.355348
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.301 62 -
Rwork0.285 1310 -
obs--81.81 %

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