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- PDB-8qt4: Crystal structure of human Sirt2 in complex with the super-slow s... -

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Basic information

Entry
Database: PDB / ID: 8qt4
TitleCrystal structure of human Sirt2 in complex with the super-slow substrate TNFn-6 and NAD+
Components
  • NAD-dependent protein deacetylase sirtuin-2
  • Peptide-based super-slow substrate TNFn-6
KeywordsHYDROLASE / Super-slow substrate / Sirtuin 2
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 / 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 / peptidyl-lysine deacetylation ...cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / negative regulation of striated muscle tissue development / negative regulation of satellite cell differentiation / 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 / peptidyl-lysine deacetylation / tubulin deacetylation / lateral loop / NLRP3 inflammasome complex assembly / negative regulation of NLRP3 inflammasome complex assembly / mitotic nuclear membrane reassembly / tubulin deacetylase activity / regulation of exit from mitosis / paranode region of axon / Schmidt-Lanterman incisure / positive regulation of fatty acid biosynthetic process / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / histone H3K14 deacetylase activity, NAD-dependent / histone H3K9 deacetylase activity, NAD-dependent / histone H4K16 deacetylase activity, NAD-dependent / histone H3K18 deacetylase activity, NAD-dependent / histone H3K56 deacetylase activity, NAD-dependent / histone H3K4 deacetylase activity, NAD-dependent / negative regulation of peptidyl-threonine phosphorylation / myelination in peripheral nervous system / rDNA heterochromatin formation / histone deacetylase activity, NAD-dependent / regulation of phosphorylation / protein deacetylation / positive regulation of oocyte maturation / Initiation of Nuclear Envelope (NE) Reformation / juxtaparanode region of axon / 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 / NAD+ poly-ADP-ribosyltransferase activity / positive regulation of execution phase of apoptosis / positive regulation of cell division / NAD+ binding / glial cell projection / subtelomeric heterochromatin formation / heterochromatin / lipid catabolic process / cellular response to epinephrine stimulus / substantia nigra development / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / centriole / 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 / heterochromatin formation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / myelin sheath / chromosome / growth cone / midbody / cellular response to oxidative stress / DNA-binding transcription factor binding / cellular response to hypoxia / perikaryon / microtubule / proteasome-mediated ubiquitin-dependent protein catabolic process / 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 / cytosol / cytoplasm
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 / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / TRIETHYLENE GLYCOL / : / 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. / Kalbas, D. / Meleshin, M. / Einsle, O. / Schutkowski, M. / Jung, M.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Research Foundation (DFG)SFB 992 Germany
German Research Foundation (DFG)295/18-1 Germany
CitationJournal: To Be Published
Title: New Super-Slow Substrates as novel Sirtuin-Inhibitors
Authors: Friedrich, F. / Kalbas, D. / Einsle, O. / Jung, M. / Schutkowski, M.
History
DepositionOct 12, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 23, 2024Provider: 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-2
B: Peptide-based super-slow substrate TNFn-6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,23113
Polymers35,4242
Non-polymers1,80711
Water5,008278
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4780 Å2
ΔGint-0 kcal/mol
Surface area14130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.056, 74.847, 55.981
Angle α, β, γ (deg.)90.00, 96.37, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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

#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: Protein/peptide Peptide-based super-slow substrate TNFn-6


Mass: 1007.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Non-polymers , 9 types, 289 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER


Mass: 209.240 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Chemical ChemComp-BU3 / (R,R)-2,3-BUTANEDIOL


Mass: 90.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2
#8: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#9: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
#10: Chemical ChemComp-WU8 / 3-dodecylsulfanyl-2,2-dimethyl-propanoic acid


Mass: 302.516 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H34O2S / Feature type: SUBJECT OF INVESTIGATION
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 278 / 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: 2.3 Å3/Da / Density % sol: 46.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 25 % (w/v) PEG 3,350 in 0.1 M Bis-Tris pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Apr 6, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.55→55.64 Å / Num. obs: 44829 / % possible obs: 99.1 % / Redundancy: 6.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.033 / Rrim(I) all: 0.085 / Χ2: 0.98 / Net I/σ(I): 14.2 / Num. measured all: 287234
Reflection shellResolution: 1.55→1.58 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.795 / Mean I/σ(I) obs: 2.8 / Num. unique obs: 2227 / CC1/2: 0.794 / Rpim(I) all: 0.333 / Rrim(I) all: 0.863 / Χ2: 1

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.55→55.64 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 17.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1877 2144 4.79 %
Rwork0.1591 --
obs0.1605 44801 99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.55→55.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2421 0 95 278 2794
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062677
X-RAY DIFFRACTIONf_angle_d0.8713624
X-RAY DIFFRACTIONf_dihedral_angle_d13.6151083
X-RAY DIFFRACTIONf_chiral_restr0.05389
X-RAY DIFFRACTIONf_plane_restr0.01463
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.55-1.590.24721550.2142878X-RAY DIFFRACTION100
1.59-1.630.22271590.20242798X-RAY DIFFRACTION100
1.63-1.670.22591330.19112878X-RAY DIFFRACTION100
1.67-1.720.23981610.18652838X-RAY DIFFRACTION100
1.72-1.770.2451430.19242864X-RAY DIFFRACTION100
1.77-1.840.21341420.17632852X-RAY DIFFRACTION100
1.84-1.910.18961290.1632902X-RAY DIFFRACTION100
1.91-20.20161430.15642855X-RAY DIFFRACTION100
2-2.10.18791490.16212797X-RAY DIFFRACTION98
2.1-2.240.17161580.15532754X-RAY DIFFRACTION97
2.24-2.410.16261170.15162665X-RAY DIFFRACTION93
2.41-2.650.17321480.15892861X-RAY DIFFRACTION99
2.65-3.030.17021290.16232889X-RAY DIFFRACTION100
3.03-3.820.18521530.14632898X-RAY DIFFRACTION100
3.82-55.640.17841250.14482928X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 9.4743 Å / Origin y: 14.5201 Å / Origin z: 7.8044 Å
111213212223313233
T0.0799 Å20.0042 Å20.0086 Å2-0.1037 Å20.0013 Å2--0.1193 Å2
L0.5626 °2-0.0327 °2-0.1236 °2-0.9591 °20.0436 °2--1.4804 °2
S0.0152 Å °-0.0743 Å °-0.0405 Å °0.0381 Å °-0.0054 Å °-0.0274 Å °-0.0103 Å °0.093 Å °-0.0141 Å °
Refinement TLS groupSelection details: all

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