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- PDB-7bot: Human SIRT2 in complex with myristoyl thiourea inhibitor, No.23 -

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Basic information

Entry
Database: PDB / ID: 7bot
TitleHuman SIRT2 in complex with myristoyl thiourea inhibitor, No.23
Components
  • NAD-dependent protein deacetylase sirtuin-2
  • myristoyl thiourea inhibitor, No.23
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / NAD-dependent deacetylase / deacylase / inhibitor complex / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / cellular lipid catabolic process / negative regulation of striated muscle tissue development / NAD-dependent histone H4K16 deacetylase activity / positive regulation of meiotic nuclear division / positive regulation of attachment of spindle microtubules to kinetochore / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / paranodal junction ...cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / cellular lipid catabolic process / negative regulation of striated muscle tissue development / NAD-dependent histone H4K16 deacetylase activity / positive regulation of meiotic nuclear division / positive regulation of attachment of spindle microtubules to kinetochore / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / paranodal junction / tubulin deacetylation / lateral loop / NLRP3 inflammasome complex assembly / peptidyl-lysine deacetylation / mitotic nuclear membrane reassembly / negative regulation of NLRP3 inflammasome complex assembly / tubulin deacetylase activity / regulation of exit from mitosis / paranode region of axon / NAD-dependent protein lysine deacetylase activity / Schmidt-Lanterman incisure / positive regulation of fatty acid biosynthetic process / myelination in peripheral nervous system / rDNA heterochromatin formation / protein acetyllysine N-acetyltransferase / chromatin silencing complex / regulation of phosphorylation / Initiation of Nuclear Envelope (NE) Reformation / protein deacetylation / NAD-dependent histone deacetylase activity / juxtaparanode region of axon / positive regulation of oocyte maturation / protein lysine deacetylase activity / meiotic spindle / response to redox state / regulation of myelination / histone acetyltransferase binding / histone deacetylase activity / 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+ ADP-ribosyltransferase activity / NAD+ binding / subtelomeric heterochromatin formation / negative regulation of reactive oxygen species metabolic process / positive regulation of DNA binding / heterochromatin / heterochromatin formation / epigenetic regulation of gene expression / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / cellular response to epinephrine stimulus / substantia nigra development / centriole / negative regulation of autophagy / meiotic cell cycle / ubiquitin binding / negative regulation of protein catabolic process / mitotic spindle / autophagy / histone deacetylase binding / spindle / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / myelin sheath / chromosome / midbody / cellular response to oxidative stress / growth cone / cellular response to hypoxia / perikaryon / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA-binding transcription factor binding / 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 / cytoplasm / cytosol
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
myristoyl thiourea inhibitor, No. 23 / N-dodecylmethanethioamide / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 Å
AuthorsKudo, N. / Olsen, C.A. / Minoru, Y.
Funding support Japan, Denmark, 5items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)JP19H05640 Japan
LundbeckfondenR289-2018-2074 Denmark
The Carlsberg Foundation2013-01-0333, CF15-011, and CF18-0442 Denmark
Novo Nordisk FoundationNF17OC002946 Denmark
European Research Council (ERC)ERC-CoG-725172 Denmark
CitationJournal: Rsc Chem Biol / Year: 2021
Title: Mechanism-based inhibitors of SIRT2: structure-activity relationship, X-ray structures, target engagement, regulation of alpha-tubulin acetylation and inhibition of breast cancer cell migration.
Authors: Nielsen, A.L. / Rajabi, N. / Kudo, N. / Lundo, K. / Moreno-Yruela, C. / Baek, M. / Fontenas, M. / Lucidi, A. / Madsen, A.S. / Yoshida, M. / Olsen, C.A.
History
DepositionMar 19, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 24, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 6, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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: myristoyl thiourea inhibitor, No.23
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0184
Polymers33,7232
Non-polymers2952
Water1,910106
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: enzyme assay
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1470 Å2
ΔGint-4 kcal/mol
Surface area13550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)35.830, 65.494, 114.889
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein NAD-dependent protein deacetylase sirtuin-2 / Regulatory protein SIR2 homolog 2 / SIR2-like protein 2


Mass: 33201.223 Da / Num. of mol.: 1 / Fragment: residues52-356, lacking292-303
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT2, SIR2L, SIR2L2 / Plasmid: pGEX-4T3 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q8IXJ6, protein acetyllysine N-acetyltransferase
#2: Protein/peptide myristoyl thiourea inhibitor, No.23


Type: Peptide-like / Class: Inhibitor / Mass: 521.633 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: The whole inhibitor comprises the peptide and the linked ligand F4R.
Source: (synth.) synthetic construct (others) / References: myristoyl thiourea inhibitor, No. 23
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-F4R / N-dodecylmethanethioamide


Type: Peptide-like / Class: Inhibitor / Mass: 229.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H27NS / Feature type: SUBJECT OF INVESTIGATION / References: myristoyl thiourea inhibitor, No. 23
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / Source method: isolated from a natural source / Formula: H2O
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: 2.03 Å3/Da / Density % sol: 39.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.15M Potassium bromide, 30% (w/v) Polyethylene glycol monomethyl ether 2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 23, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.54→20 Å / Num. obs: 40773 / % possible obs: 99.8 % / Redundancy: 13 % / Rmerge(I) obs: 0.051 / Net I/σ(I): 19.8
Reflection shellResolution: 1.54→1.98 Å / Rmerge(I) obs: 0.953 / Num. unique obs: 39028 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0258refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Y6L

4y6l


Resolution: 1.7→20 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.905 / SU B: 4.068 / SU ML: 0.132 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.151 / ESU R Free: 0.158 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3196 1527 5 %RANDOM
Rwork0.2508 ---
obs0.2541 29045 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 108.97 Å2 / Biso mean: 52.484 Å2 / Biso min: 23.77 Å2
Baniso -1Baniso -2Baniso -3
1--1.57 Å20 Å20 Å2
2---0.85 Å20 Å2
3---2.42 Å2
Refinement stepCycle: final / Resolution: 1.7→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2206 0 53 106 2365
Biso mean--79.6 45.47 -
Num. residues----277
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0122305
X-RAY DIFFRACTIONr_angle_refined_deg1.3071.6633100
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7945272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.69221.754114
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.22815406
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.1651515
X-RAY DIFFRACTIONr_chiral_restr0.1010.2289
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021719
LS refinement shellResolution: 1.7→1.744 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.315 110 -
Rwork0.301 2087 -
all-2197 -
obs--100 %

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