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

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Basic information

Entry
Database: PDB / ID: 8qtu
TitleCrystal structure of human Sirt2 in complex with the super-slow substrate TNFn-3 and NAD+
Components
  • NAD-dependent protein deacetylase sirtuin-2
  • Peptide-based super-slow substrate TNFn-3
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 / 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 ...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 / tubulin deacetylation / paranodal junction / lateral loop / NLRP3 inflammasome complex assembly / peptidyl-lysine deacetylation / 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 / NAD-dependent protein lysine deacetylase activity / positive regulation of fatty acid biosynthetic process / rDNA heterochromatin formation / protein acetyllysine N-acetyltransferase / myelination in peripheral nervous system / histone deacetylase activity, NAD-dependent / chromatin silencing complex / Initiation of Nuclear Envelope (NE) Reformation / protein deacetylation / positive regulation of oocyte maturation / regulation of phosphorylation / juxtaparanode region of axon / protein lysine deacetylase activity / meiotic spindle / response to redox state / regulation of myelination / histone deacetylase activity / histone acetyltransferase binding / positive regulation of DNA binding / negative regulation of fat cell differentiation / negative regulation of peptidyl-threonine phosphorylation / positive regulation of execution phase of apoptosis / glial cell projection / positive regulation of cell division / NAD+-protein poly-ADP-ribosyltransferase activity / NAD+ binding / negative regulation of reactive oxygen species metabolic process / subtelomeric heterochromatin formation / heterochromatin / cellular response to epinephrine stimulus / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / substantia nigra development / centriole / epigenetic regulation of gene expression / negative regulation of autophagy / ubiquitin binding / meiotic cell cycle / negative regulation of protein catabolic process / heterochromatin formation / mitotic spindle / histone deacetylase binding / autophagy / spindle / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / myelin sheath / chromosome / cellular response to oxidative stress / cellular response to hypoxia / growth cone / midbody / perikaryon / DNA-binding transcription factor binding / proteasome-mediated ubiquitin-dependent protein catabolic process / microtubule / chromosome, telomeric region / regulation of cell cycle / cell division / innate immune response / 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
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / : / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 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 13, 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 super-slow substrate TNFn-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5196
Polymers35,4262
Non-polymers1,0934
Water3,189177
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3100 Å2
ΔGint-15 kcal/mol
Surface area13760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.292, 74.689, 56.197
Angle α, β, γ (deg.)90.00, 97.66, 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-3


Mass: 1009.113 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Non-polymers , 5 types, 181 molecules

#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-WWE / 3-dodecylsulfanyl-3-methyl-butanoic acid


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


Mass: 18.015 Da / Num. of mol.: 177 / 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: 2.24 Å3/Da / Density % sol: 45.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 21.5 % (w/v) PEG 3,350 in 0.1 M Bis-Tris pH 6.25

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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: Jun 22, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.8→55.7 Å / Num. obs: 28715 / % possible obs: 98.6 % / Redundancy: 6.9 % / CC1/2: 0.996 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.027 / Rrim(I) all: 0.072 / Χ2: 0.99 / Net I/σ(I): 16.9 / Num. measured all: 197457
Reflection shellResolution: 1.8→1.84 Å / Redundancy: 7.1 % / Rmerge(I) obs: 0.616 / Mean I/σ(I) obs: 3.3 / Num. unique obs: 1697 / CC1/2: 0.912 / Rpim(I) all: 0.247 / Rrim(I) all: 0.664 / Χ2: 0.99

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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: 1.8→37.95 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.09 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2067 1438 5.01 %
Rwork0.1842 --
obs0.1854 28683 98.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.8→37.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 49 177 2578
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082558
X-RAY DIFFRACTIONf_angle_d0.943480
X-RAY DIFFRACTIONf_dihedral_angle_d6.825438
X-RAY DIFFRACTIONf_chiral_restr0.059380
X-RAY DIFFRACTIONf_plane_restr0.012449
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.860.29751480.22962720X-RAY DIFFRACTION99
1.86-1.940.24321290.23612732X-RAY DIFFRACTION99
1.94-2.030.2681490.21542739X-RAY DIFFRACTION99
2.03-2.130.25751410.19072746X-RAY DIFFRACTION100
2.13-2.270.23721430.18942753X-RAY DIFFRACTION99
2.27-2.440.2191430.19282708X-RAY DIFFRACTION99
2.44-2.690.21391540.19332494X-RAY DIFFRACTION91
2.69-3.080.22891420.19852764X-RAY DIFFRACTION100
3.08-3.880.18581270.17332800X-RAY DIFFRACTION100
3.88-37.950.1731620.16382789X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 8.911 Å / Origin y: 13.8497 Å / Origin z: 7.5139 Å
111213212223313233
T0.1613 Å20.0264 Å20.0094 Å2-0.1676 Å20.0041 Å2--0.1915 Å2
L0.9524 °20.0493 °2-0.1948 °2-1.7993 °20.2615 °2--2.4531 °2
S0.0509 Å °-0.0847 Å °-0.0423 Å °0.2504 Å °-0.0308 Å °-0.0138 Å °0.0622 Å °0.2227 Å °-0.0237 Å °
Refinement TLS groupSelection details: all

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