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- PDB-5mat: Structure of human Sirtuin 2 in complex with a selective thienopy... -

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Basic information

Entry
Database: PDB / ID: 5mat
TitleStructure of human Sirtuin 2 in complex with a selective thienopyrimidinone based inhibitor
ComponentsNAD-dependent protein deacetylase sirtuin-2
KeywordsHYDROLASE / NAD-dependent protein deacylase / sirtuin / inhibitor complex
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 / paranodal junction ...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 / 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 / paranode region of axon / regulation of exit from mitosis / positive regulation of fatty acid biosynthetic process / Schmidt-Lanterman incisure / negative regulation of peptidyl-threonine phosphorylation / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / regulation of phosphorylation / myelination in peripheral nervous system / rDNA heterochromatin formation / protein deacetylation / histone deacetylase activity, NAD-dependent / positive regulation of oocyte maturation / juxtaparanode region of axon / Initiation of Nuclear Envelope (NE) Reformation / chromatin silencing complex / meiotic spindle / protein lysine deacetylase activity / response to redox state / regulation of myelination / positive regulation of DNA binding / histone deacetylase activity / negative regulation of fat cell differentiation / histone acetyltransferase binding / negative regulation of reactive oxygen species metabolic process / positive regulation of cell division / NAD+ poly-ADP-ribosyltransferase activity / NAD+ binding / positive regulation of execution phase of apoptosis / glial cell projection / subtelomeric heterochromatin formation / heterochromatin / lipid catabolic process / cellular response to epinephrine stimulus / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / centriole / substantia nigra development / 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 / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / heterochromatin formation / myelin sheath / chromosome / growth cone / cellular response to oxidative stress / midbody / perikaryon / cellular response to hypoxia / DNA-binding transcription factor binding / proteasome-mediated ubiquitin-dependent protein catabolic process / microtubule / 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 / cytoplasm / cytosol
Similarity search - Function
Sirtuin, class I / SIR2/SIRT2 'Small Domain' / SIR2/SIRT2 'Small Domain' / Sirtuin, catalytic core small domain superfamily / Sirtuin family / : / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain ...Sirtuin, class I / SIR2/SIRT2 'Small Domain' / SIR2/SIRT2 'Small Domain' / Sirtuin, catalytic core small domain superfamily / Sirtuin family / : / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / TPP-binding domain / DHS-like NAD/FAD-binding domain superfamily / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-7KJ / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.069 Å
AuthorsMoniot, S. / Steegborn, C.
Funding support Germany, 1items
OrganizationGrant numberCountry
Alzheimer Forschung Initiative e.V.14834 Germany
CitationJournal: J. Med. Chem. / Year: 2017
Title: Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket.
Authors: Sundriyal, S. / Moniot, S. / Mahmud, Z. / Yao, S. / Di Fruscia, P. / Reynolds, C.R. / Dexter, D.T. / Sternberg, M.J. / Lam, E.W. / Steegborn, C. / Fuchter, M.J.
History
DepositionNov 4, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 8, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2017Group: Database references
Revision 1.2Jan 17, 2024Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_audit_support / pdbx_initial_refinement_model / refine
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization / _refine.pdbx_diffrn_id

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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
C: NAD-dependent protein deacetylase sirtuin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,17221
Polymers68,7192
Non-polymers2,45319
Water7,927440
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5110 Å2
ΔGint-160 kcal/mol
Surface area27490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.683, 68.560, 78.462
Angle α, β, γ (deg.)90.000, 95.660, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 2 molecules AC

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


Mass: 34359.676 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: N-terminal residues HM are cloning artifacts / Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT2, SIR2L, SIR2L2 / Plasmid: pET19 modified / Details (production host): His6-SUMO N-terminal fusion tag / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): codon plus
References: UniProt: Q8IXJ6, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides

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Non-polymers , 6 types, 459 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-7KJ / (7~{R})-7-[(3,5-dimethyl-1,2-oxazol-4-yl)methylamino]-3-[(4-methoxynaphthalen-1-yl)methyl]-5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-4-one


Mass: 500.612 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H28N4O3S
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#6: Chemical ChemComp-P6G / HEXAETHYLENE GLYCOL / POLYETHYLENE GLYCOL PEG400


Mass: 282.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H26O7 / Comment: precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 440 / Source method: isolated from a natural source / Formula: H2O

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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: 2.32 Å3/Da / Density % sol: 47.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.83 / Details: 2.6M ammonium sulfate, 5% PEG 300, 0.1 M MES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 6, 2016
RadiationMonochromator: Si-111 crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.07→45.17 Å / Num. obs: 38188 / % possible obs: 98.9 % / Redundancy: 2.7 % / Biso Wilson estimate: 29.7 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.088 / Net I/σ(I): 9.82
Reflection shellResolution: 2.07→2.19 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.424 / Mean I/σ(I) obs: 2.37 / CC1/2: 0.77 / % possible all: 98.1

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Processing

Software
NameClassification
PHENIXrefinement
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4rmg

4rmg


Resolution: 2.069→44.89 Å / Redundancy reflection all: 98.88 / Cross valid method: FREE R-VALUE
RfactorNum. reflectionSelection details
Rwork0.1646 --
obs0.2049 38175 -
Rfree-1910 RANDOM
Displacement parametersBiso mean: 32.87 Å2
Refinement stepCycle: LAST / Resolution: 2.069→44.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4758 0 140 440 5338
LS refinement shellResolution: 2.069→2.143 Å / Redundancy reflection all: 98.09
RfactorNum. reflection
Rfree0.3098 188
Rwork0.2485 -
all-3754

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