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- PDB-4l3o: Crystal Structure of SIRT2 in complex with the macrocyclic peptid... -

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Basic information

Entry
Database: PDB / ID: 4l3o
TitleCrystal Structure of SIRT2 in complex with the macrocyclic peptide S2iL5
Components
  • NAD-dependent protein deacetylase sirtuin-2
  • cyclic peptide S2iL5
KeywordsHYDROLASE/HYDROLASE INHIBITOR / macrocyclic peptide / structural change / HYDROLASE-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 / positive regulation of meiotic nuclear division / NAD-dependent histone H4K16 deacetylase activity / : / positive regulation of attachment of spindle microtubules to kinetochore / tubulin deacetylation / NAD-dependent protein demyristoylase activity ...cellular response to caloric restriction / negative regulation of oligodendrocyte progenitor proliferation / cellular lipid catabolic process / negative regulation of striated muscle tissue development / positive regulation of meiotic nuclear division / NAD-dependent histone H4K16 deacetylase activity / : / positive regulation of attachment of spindle microtubules to kinetochore / tubulin deacetylation / NAD-dependent protein demyristoylase activity / NAD-dependent protein depalmitoylase activity / paranodal junction / lateral loop / NLRP3 inflammasome complex assembly / peptidyl-lysine deacetylation / mitotic nuclear membrane reassembly / negative regulation of NLRP3 inflammasome complex assembly / tubulin deacetylase activity / paranode region of axon / Schmidt-Lanterman incisure / regulation of exit from mitosis / myelination in peripheral nervous system / positive regulation of fatty acid biosynthetic process / NAD-dependent protein lysine deacetylase activity / rDNA heterochromatin formation / protein acetyllysine N-acetyltransferase / NAD-dependent histone deacetylase activity / chromatin silencing complex / regulation of phosphorylation / Initiation of Nuclear Envelope (NE) Reformation / protein deacetylation / juxtaparanode region of axon / positive regulation of oocyte maturation / protein lysine deacetylase activity / meiotic spindle / response to redox state / histone deacetylase activity / regulation of myelination / histone acetyltransferase binding / negative regulation of fat cell differentiation / positive regulation of execution phase of apoptosis / negative regulation of peptidyl-threonine phosphorylation / glial cell projection / subtelomeric heterochromatin formation / positive regulation of cell division / NAD+ ADP-ribosyltransferase activity / NAD+ binding / 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 / spindle / autophagy / histone deacetylase binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / myelin sheath / cellular response to oxidative stress / chromosome / midbody / 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 / centrosome / negative regulation of DNA-templated transcription / 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 / 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
cyclic peptide S2iL5 / NAD-dependent protein deacetylase sirtuin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.518 Å
AuthorsYamagata, K. / Nishimasu, H. / Ishitani, R. / Nureki, O.
CitationJournal: Structure / Year: 2013
Title: Structural Basis for Potent Inhibition of SIRT2 Deacetylase by a Macrocyclic Peptide Inducing Dynamic Structural Change
Authors: Yamagata, K. / Goto, Y. / Nishimasu, H. / Morimoto, J. / Ishitani, R. / Dohmae, N. / Takeda, N. / Nagai, R. / Komuro, I. / Suga, H. / Nureki, O.
History
DepositionJun 6, 2013Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Feb 19, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_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
B: NAD-dependent protein deacetylase sirtuin-2
C: NAD-dependent protein deacetylase sirtuin-2
D: NAD-dependent protein deacetylase sirtuin-2
E: cyclic peptide S2iL5
F: cyclic peptide S2iL5
G: cyclic peptide S2iL5
H: cyclic peptide S2iL5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,34620
Polymers145,0558
Non-polymers1,29112
Water9,134507
1
A: NAD-dependent protein deacetylase sirtuin-2
E: cyclic peptide S2iL5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5244
Polymers36,2642
Non-polymers2612
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1920 Å2
ΔGint-8 kcal/mol
Surface area14480 Å2
MethodPISA
2
B: NAD-dependent protein deacetylase sirtuin-2
F: cyclic peptide S2iL5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5865
Polymers36,2642
Non-polymers3233
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1900 Å2
ΔGint-9 kcal/mol
Surface area14260 Å2
MethodPISA
3
C: NAD-dependent protein deacetylase sirtuin-2
G: cyclic peptide S2iL5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7117
Polymers36,2642
Non-polymers4475
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1930 Å2
ΔGint-8 kcal/mol
Surface area14310 Å2
MethodPISA
4
D: NAD-dependent protein deacetylase sirtuin-2
H: cyclic peptide S2iL5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5244
Polymers36,2642
Non-polymers2612
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1930 Å2
ΔGint-7 kcal/mol
Surface area14220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.180, 135.613, 148.830
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein / Protein/peptide , 2 types, 8 molecules ABCDEFGH

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


Mass: 34219.512 Da / Num. of mol.: 4 / Fragment: UNP residues 55-356
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SIRT2 / Plasmid: pET-28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q8IXJ6, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Protein/peptide
cyclic peptide S2iL5


Type: Cyclic peptide / Class: Enzyme inhibitor / Mass: 2044.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Details: This sequence is chemically synthesized / References: cyclic peptide S2iL5

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Non-polymers , 4 types, 519 molecules

#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 507 / 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: 3.17 Å3/Da / Density % sol: 61.22 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 8.5% PEG 4000, 0.1M MES-NaOH, 0.1M Li2SO4, 0.1M NaCl, pH 7.0, vapor diffusion, sitting drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32XU / Wavelength: 1 Å
DetectorDetector: CCD / Date: Feb 2, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.518→50 Å / Num. obs: 61389 / Biso Wilson estimate: 27.09 Å2

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Processing

Software
NameVersionClassificationNB
PHENIX1.7.2_869refinement
PDB_EXTRACT3.11data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1J8F

1j8f


Resolution: 2.518→46.59 Å / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8251 / SU ML: 0.76 / σ(F): 1.5 / Phase error: 24.97 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2629 6136 10 %
Rwork0.211 --
obs0.2162 61346 97.13 %
Solvent computationShrinkage radii: 0.98 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 12.83 Å2 / ksol: 0.299 e/Å3
Displacement parametersBiso max: 109.51 Å2 / Biso mean: 35.9615 Å2 / Biso min: 7.56 Å2
Baniso -1Baniso -2Baniso -3
1-5.8184 Å2-0 Å2-0 Å2
2---1.0871 Å2-0 Å2
3----4.7313 Å2
Refinement stepCycle: LAST / Resolution: 2.518→46.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9899 0 68 507 10474
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00310223
X-RAY DIFFRACTIONf_angle_d0.61913766
X-RAY DIFFRACTIONf_chiral_restr0.0461472
X-RAY DIFFRACTIONf_plane_restr0.0021750
X-RAY DIFFRACTIONf_dihedral_angle_d12.793838
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5179-2.54650.37221070.3049961106852
2.5465-2.57650.35072030.29071823202697
2.5765-2.60790.30592050.27841849205498
2.6079-2.64090.3542010.29071820202198
2.6409-2.67570.34582040.28391836204098
2.6757-2.71230.34082020.26481809201197
2.7123-2.75110.32862060.2561849205598
2.7511-2.79210.33262010.25431817201898
2.7921-2.83580.29552070.24211869207698
2.8358-2.88220.29632060.24141841204798
2.8822-2.93190.30612010.23871816201798
2.9319-2.98520.30982070.23271860206799
2.9852-3.04260.29822060.2191851205799
3.0426-3.10470.25742050.21821849205498
3.1047-3.17220.30332060.22071855206199
3.1722-3.2460.27022090.22071870207999
3.246-3.32720.2782060.22031862206899
3.3272-3.41710.2892070.21391866207399
3.4171-3.51760.26592090.2041877208699
3.5176-3.63110.26062110.21451899211099
3.6311-3.76080.24152040.19551843204799
3.7608-3.91130.23762110.18891891210299
3.9113-4.08930.25262120.177119072119100
4.0893-4.30470.20982100.16461896210699
4.3047-4.57420.20652090.16081881209099
4.5742-4.9270.20952120.16051906211899
4.927-5.42220.20582130.18491915212899
5.4222-6.20520.25922130.20851915212899
6.2052-7.81190.2532160.19961944216099
7.8119-46.59830.20722270.19872033226099

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