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- PDB-5dy4: Crystal structure of human Sirt2 in complex with a brominated 2nd... -

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Basic information

Entry
Database: PDB / ID: 5dy4
TitleCrystal structure of human Sirt2 in complex with a brominated 2nd generation SirReal inhibitor and NAD+
ComponentsNAD-dependent protein deacetylase sirtuin-2
KeywordsHYDROLASE / hydrolase 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 / positive regulation of oocyte maturation / juxtaparanode region of axon / 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+-protein poly-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 / 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 ...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-5GN / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.77 Å
AuthorsRumpf, T. / Gerhardt, S. / Einsle, O. / Jung, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationJu295/8-1 Germany
CitationJournal: J.Med.Chem. / Year: 2016
Title: Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study.
Authors: Schiedel, M. / Rumpf, T. / Karaman, B. / Lehotzky, A. / Olah, J. / Gerhardt, S. / Ovadi, J. / Sippl, W. / Einsle, O. / Jung, M.
History
DepositionSep 24, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jan 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 20, 2016Group: Database references
Revision 1.2Mar 9, 2016Group: Database references
Revision 1.3Jan 10, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6454
Polymers34,4171
Non-polymers1,2283
Water3,297183
1
A: NAD-dependent protein deacetylase sirtuin-2
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)71,2908
Polymers68,8332
Non-polymers2,4576
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area5880 Å2
ΔGint-43 kcal/mol
Surface area25520 Å2
MethodPISA
2


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-3 kcal/mol
Surface area14490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.303, 55.432, 96.176
Angle α, β, γ (deg.)90.00, 114.91, 90.00
Int Tables number5
Space group name H-MI121
Components on special symmetry positions
IDModelComponents
11A-663-

HOH

21A-683-

HOH

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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: residues 56-356
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT2, SIR2L, SIR2L2 / Plasmid: modified pET15b / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Codonplus RIPL
References: UniProt: Q8IXJ6, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-5GN / N-{5-[(7-bromonaphthalen-1-yl)methyl]-1,3-thiazol-2-yl}-2-[(4,6-dimethylpyrimidin-2-yl)sulfanyl]acetamide


Mass: 499.446 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H19BrN4OS2
#4: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 183 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.96 Å3/Da / Density % sol: 58.46 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 27 % PEG 3350 / PH range: 7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 30, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.77→46.78 Å / Num. obs: 38622 / % possible obs: 98.2 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.095 / Net I/σ(I): 10.3
Reflection shellResolution: 1.77→1.81 Å / Redundancy: 6.9 % / Rmerge(I) obs: 2.05 / Mean I/σ(I) obs: 1 / % possible all: 98.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RMG

4rmg


Resolution: 1.77→46.78 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.95 / SU B: 5.857 / SU ML: 0.094 / Cross valid method: THROUGHOUT / ESU R: 0.101 / ESU R Free: 0.104 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21286 1913 5 %RANDOM
Rwork0.17494 ---
obs0.17686 36691 97.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.455 Å2
Baniso -1Baniso -2Baniso -3
1--1.09 Å20 Å2-1 Å2
2--1.34 Å20 Å2
3---0.47 Å2
Refinement stepCycle: 1 / Resolution: 1.77→46.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2391 0 75 183 2649
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0192531
X-RAY DIFFRACTIONr_bond_other_d0.0020.022377
X-RAY DIFFRACTIONr_angle_refined_deg1.6461.9943420
X-RAY DIFFRACTIONr_angle_other_deg1.0213.0015489
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1555299
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.24923.67109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.63315438
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2051515
X-RAY DIFFRACTIONr_chiral_restr0.0980.2364
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212906
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02574
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4842.7361204
X-RAY DIFFRACTIONr_mcbond_other1.4842.7361203
X-RAY DIFFRACTIONr_mcangle_it2.4214.0871500
X-RAY DIFFRACTIONr_mcangle_other2.4214.0871501
X-RAY DIFFRACTIONr_scbond_it1.8973.061327
X-RAY DIFFRACTIONr_scbond_other1.8963.061328
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.1014.4821921
X-RAY DIFFRACTIONr_long_range_B_refined5.08822.9312946
X-RAY DIFFRACTIONr_long_range_B_other5.02722.5772872
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.77→1.816 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 142 -
Rwork0.306 2726 -
obs--97.98 %
Refinement TLS params.Method: refined / Origin x: -15.9435 Å / Origin y: -26.8785 Å / Origin z: -0.054 Å
111213212223313233
T0.012 Å20.0244 Å20.009 Å2-0.0602 Å20.0255 Å2--0.0199 Å2
L0.4732 °20.0327 °20.278 °2-0.0523 °2-0.0799 °2--0.3732 °2
S0.0147 Å °0.0146 Å °0.0122 Å °0.0019 Å °0.0237 Å °0.0269 Å °0.0116 Å °-0.0097 Å °-0.0385 Å °

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