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- PDB-8qt8: Crystal structure of human Sirt2 in complex with a TNFa-Myr analo... -

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Basic information

Entry
Database: PDB / ID: 8qt8
TitleCrystal structure of human Sirt2 in complex with a TNFa-Myr analogue TNFn-34
Components
  • NAD-dependent protein deacetylase sirtuin-2
  • Peptide-based TNFa-Myr analogue TNFn-34
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
: / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 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: Schutkowski, M. / Kalbas, D. / Einsle, O. / Schutkowski, M. / Jung, 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

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Assembly

Deposited unit
A: NAD-dependent protein deacetylase sirtuin-2
B: Peptide-based TNFa-Myr analogue TNFn-34
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7644
Polymers35,4242
Non-polymers3402
Water3,225179
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1710 Å2
ΔGint-5 kcal/mol
Surface area14070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.106, 73.339, 55.229
Angle α, β, γ (deg.)90.00, 95.17, 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: Protein/peptide Peptide-based TNFa-Myr analogue TNFn-34


Mass: 1007.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-WWK / 3-dodecylsulfanylpropanoic acid


Mass: 274.463 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H30O2S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 179 / Source method: isolated from a natural source / Formula: H2O
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: 2.14 Å3/Da / Density % sol: 42.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 19 % (w/v) PEG 3,350 in 0.1 M Bis-Tris pH 6.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9188 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 9, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9188 Å / Relative weight: 1
ReflectionResolution: 1.65→44 Å / Num. obs: 34505 / % possible obs: 99.9 % / Redundancy: 6.7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.035 / Rrim(I) all: 0.091 / Χ2: 1.02 / Net I/σ(I): 12.9 / Num. measured all: 232753
Reflection shellResolution: 1.65→1.68 Å / Redundancy: 7 % / Rmerge(I) obs: 0.837 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 1718 / CC1/2: 0.804 / Rpim(I) all: 0.339 / Rrim(I) all: 0.904 / Χ2: 0.95

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→44 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.28 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2121 1744 5.06 %
Rwork0.1855 --
obs0.1868 34478 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.65→44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2373 0 1 179 2553
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092467
X-RAY DIFFRACTIONf_angle_d1.0593330
X-RAY DIFFRACTIONf_dihedral_angle_d7.04360
X-RAY DIFFRACTIONf_chiral_restr0.063361
X-RAY DIFFRACTIONf_plane_restr0.009428
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.70.3281370.26412764X-RAY DIFFRACTION100
1.7-1.750.27661460.23972694X-RAY DIFFRACTION100
1.75-1.820.24731670.23632712X-RAY DIFFRACTION100
1.82-1.890.22631560.1972697X-RAY DIFFRACTION100
1.89-1.970.25281320.19382751X-RAY DIFFRACTION100
1.97-2.080.21451390.19082702X-RAY DIFFRACTION100
2.08-2.210.2281500.19332731X-RAY DIFFRACTION100
2.21-2.380.23841510.18392705X-RAY DIFFRACTION100
2.38-2.620.21541440.19182731X-RAY DIFFRACTION100
2.62-30.24411600.19562723X-RAY DIFFRACTION100
3-3.780.19761390.17822727X-RAY DIFFRACTION100
3.78-440.16181230.16172797X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 7.2089 Å / Origin y: 16.6977 Å / Origin z: 18.8811 Å
111213212223313233
T0.1664 Å20.0063 Å2-0.0151 Å2-0.1448 Å2-0.008 Å2--0.1523 Å2
L0.6607 °2-0.1503 °2-0.2009 °2-0.7 °2-0.3225 °2--1.4817 °2
S0.0472 Å °0.1341 Å °-0.0498 Å °-0.0849 Å °0.0238 Å °0.0921 Å °-0.0403 Å °-0.2056 Å °-0.0773 Å °
Refinement TLS groupSelection details: all

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