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- PDB-4buz: SIR2 COMPLEX STRUCTURE MIXTURE OF EX-527 INHIBITOR AND REACTION P... -

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Basic information

Entry
Database: PDB / ID: 4buz
TitleSIR2 COMPLEX STRUCTURE MIXTURE OF EX-527 INHIBITOR AND REACTION PRODUCTS OR OF REACTION SUBSTRATES P53 PEPTIDE AND NAD
Components
  • CELLULAR TUMOR ANTIGEN P53
  • NAD-DEPENDENT PROTEIN DEACETYLASE
KeywordsHYDROLASE / NAD-DEPENDENT DEACETYLASE / SIRTUIN / INHIBITOR COMPLEX / EX-527 / RUNNING REACTION
Function / homology
Function and homology information


protein acetyllysine N-acetyltransferase / histone deacetylase activity, NAD-dependent / negative regulation of helicase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator ...protein acetyllysine N-acetyltransferase / histone deacetylase activity, NAD-dependent / negative regulation of helicase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / Activation of NOXA and translocation to mitochondria / regulation of cell cycle G2/M phase transition / oligodendrocyte apoptotic process / negative regulation of miRNA processing / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / mRNA transcription / bone marrow development / positive regulation of programmed necrotic cell death / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / homolactic fermentation / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / histone deacetylase regulator activity / regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / mitochondrial DNA repair / T cell lineage commitment / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / thymocyte apoptotic process / B cell lineage commitment / TP53 Regulates Transcription of Caspase Activators and Caspases / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / negative regulation of mitophagy / negative regulation of DNA replication / Zygotic genome activation (ZGA) / Association of TriC/CCT with target proteins during biosynthesis / PI5P Regulates TP53 Acetylation / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / necroptotic process / positive regulation of release of cytochrome c from mitochondria / negative regulation of telomere maintenance via telomerase / SUMOylation of transcription factors / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TFIID-class transcription factor complex binding / intrinsic apoptotic signaling pathway by p53 class mediator / rRNA transcription / negative regulation of reactive oxygen species metabolic process / Transcriptional Regulation by VENTX / cellular response to UV-C / replicative senescence / viral process / general transcription initiation factor binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / NAD+ binding / positive regulation of RNA polymerase II transcription preinitiation complex assembly / cellular response to actinomycin D / neuroblast proliferation / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of execution phase of apoptosis / Pyroptosis / hematopoietic stem cell differentiation / embryonic organ development / response to X-ray / chromosome organization / type II interferon-mediated signaling pathway / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / hematopoietic progenitor cell differentiation / negative regulation of fibroblast proliferation / positive regulation of cardiac muscle cell apoptotic process / core promoter sequence-specific DNA binding / glial cell proliferation / negative regulation of stem cell proliferation / cellular response to glucose starvation / cis-regulatory region sequence-specific DNA binding / mitophagy / Regulation of TP53 Activity through Acetylation / positive regulation of intrinsic apoptotic signaling pathway / response to salt stress / 14-3-3 protein binding / mitotic G1 DNA damage checkpoint signaling / negative regulation of proteolysis / cardiac muscle cell apoptotic process / gastrulation
Similarity search - Function
Sirtuin, class U / 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. / Cellular tumor antigen p53, transactivation domain 2 ...Sirtuin, class U / 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. / Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / TPP-binding domain / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / DHS-like NAD/FAD-binding domain superfamily / p53-like transcription factor, DNA-binding / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / 2'-O-ACETYL ADENOSINE-5-DIPHOSPHORIBOSE / Chem-OCZ / Cellular tumor antigen p53 / NAD-dependent protein deacetylase
Similarity search - Component
Biological speciesTHERMOTOGA MARITIMA (bacteria)
HOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsWeyand, M. / Lakshminarasimhan, M. / Gertz, M. / Steegborn, C.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2013
Title: Ex-527 Inhibits Sirtuins by Exploiting Their Unique Nad+-Dependent Deacetylation Mechanism
Authors: Gertz, M. / Fischer, F. / Nguyen, G.T.T. / Lakshminarasimhan, M. / Schutkowski, M. / Weyand, M. / Steegborn, C.
History
DepositionJun 24, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 17, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2013Group: Database references
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _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_conn_type.id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NAD-DEPENDENT PROTEIN DEACETYLASE
P: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,3447
Polymers28,7032
Non-polymers1,6415
Water3,603200
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-6.6 kcal/mol
Surface area11320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.750, 59.920, 109.030
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AP

#1: Protein NAD-DEPENDENT PROTEIN DEACETYLASE / REGULATORY PROTEIN SIR2 HOMOLOG / SIR2TM / NAD-DEPENDENT PROTEIN DEACETYLASE SIR2


Mass: 27569.793 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) THERMOTOGA MARITIMA (bacteria) / Plasmid: PET11A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q9WYW0, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Protein/peptide CELLULAR TUMOR ANTIGEN P53 / ANTIGEN NY-CO-13 / PHOSPHOPROTEIN P53 / TUMOR SUPPRESSOR P53 / P53


Mass: 1133.452 Da / Num. of mol.: 1 / Fragment: RESIDUES 379-386 / Source method: obtained synthetically / Details: ACETYLATED P53 LYS-382 / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P04637

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Non-polymers , 6 types, 205 molecules

#3: Chemical ChemComp-OCZ / (1S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1- carboxamide


Mass: 248.708 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H13ClN2O
#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: Chemical ChemComp-OAD / 2'-O-ACETYL ADENOSINE-5-DIPHOSPHORIBOSE


Type: RNA linking / Mass: 601.352 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H25N5O15P2
#6: Chemical ChemComp-ZN / ZINC ION


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


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 200 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
Nonpolymer detailsTHE INHIBITOR OCZ (A1247), ACETYLATED LYSINE ALY (P 382) AND SUBSTRATE ACETYL RIBOSE OAD (A 1249) ...THE INHIBITOR OCZ (A1247), ACETYLATED LYSINE ALY (P 382) AND SUBSTRATE ACETYL RIBOSE OAD (A 1249) BIND ALTERNATIVELY TO THE SAME BINDING SITE GIVING RISE TO MICROHETEROGENEITY.

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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: 2.66 Å3/Da / Density % sol: 53.76 % / Description: NONE
Crystal growpH: 8.5 / Details: 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91998
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Sep 14, 2011 / Details: COLLIMATOR
RadiationMonochromator: SI(111) MONOCHROMATOR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91998 Å / Relative weight: 1
ReflectionResolution: 1.9→25 Å / Num. obs: 24822 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 4.4 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 20.7
Reflection shellResolution: 1.9→2 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 3.5 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2H4F

2h4f


Resolution: 1.9→40.32 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.939 / SU B: 4.883 / SU ML: 0.077 / Cross valid method: THROUGHOUT / ESU R: 0.124 / ESU R Free: 0.118 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.19357 1241 5 %RANDOM
Rwork0.1593 ---
obs0.16104 23580 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.528 Å2
Baniso -1Baniso -2Baniso -3
1-0.99 Å20 Å20 Å2
2---0.16 Å20 Å2
3----0.83 Å2
Refinement stepCycle: LAST / Resolution: 1.9→40.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1928 0 105 200 2233
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.022183
X-RAY DIFFRACTIONr_bond_other_d0.0030.022112
X-RAY DIFFRACTIONr_angle_refined_deg2.0652.0472978
X-RAY DIFFRACTIONr_angle_other_deg1.013.0084885
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1875269
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.25323.89595
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.02215389
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6761516
X-RAY DIFFRACTIONr_chiral_restr0.1180.2338
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212391
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02485
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_it2.1221.8191010
X-RAY DIFFRACTIONr_mcbond_other2.1151.8141009
X-RAY DIFFRACTIONr_mcangle_it3.2582.6941268
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.8292.2611173
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.239 91 -
Rwork0.208 1746 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.3967-0.0641-0.09380.9262-0.17961.4542-0.07080.0095-0.0642-0.07650.0251-0.00170.1222-0.03310.04570.0277-0.00970.01880.0214-0.01030.0304-3.22339.0989-9.9847
20.6579-0.34130.60451.705-0.9342.5823-0.00680.09340.09520.1389-0.1019-0.2174-0.2149-0.06160.10870.0672-0.00140.00260.03430.02170.04225.10535.9194-15.1737
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 36
2X-RAY DIFFRACTION1A75 - 115
3X-RAY DIFFRACTION1A166 - 246
4X-RAY DIFFRACTION2A44 - 73
5X-RAY DIFFRACTION2A116 - 161

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