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- PDB-2v5w: Crystal structure of HDAC8-substrate complex -

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Basic information

Entry
Database: PDB / ID: 2v5w
TitleCrystal structure of HDAC8-substrate complex
Components
  • GLYCYL-GLYCYL-GLYCINE
  • HISTONE DEACETYLASE 8
  • PEPTIDIC SUBSTRATE
KeywordsHYDROLASE/HYDROLASE SUBSTRATE / HISTONE DEACETYLASE / CHROMATIN REGULATOR / P53 / HDAC / HDAC8 / NUCLEUS / REPRESSOR / HYDROLASE / NUCLEAR PROTEIN / PEPTIDIC SUBSTRATE / TRANSCRIPTION REGULATION / CHROMATIN / TRANSCRIPTION / DEACETYLATION / HYDROLASE-HYDROLASE SUBSTRATE COMPLEX
Function / homology
Function and homology information


histone decrotonylase activity / histone deacetylase / protein lysine deacetylase 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 ...histone decrotonylase activity / histone deacetylase / protein lysine deacetylase 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 / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / negative regulation of helicase activity / regulation of cell cycle G2/M phase transition / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / oxidative stress-induced premature senescence / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / regulation of telomere maintenance / circadian behavior / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / histone deacetylase regulator activity / germ cell nucleus / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / regulation of DNA damage response, signal transduction by p53 class mediator / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / negative regulation of glial cell proliferation / mitotic sister chromatid cohesion / negative regulation of neuroblast proliferation / Regulation of TP53 Activity through Association with Co-factors / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / histone deacetylase activity / nuclear chromosome / mitochondrial DNA repair / T cell lineage commitment / negative regulation of DNA replication / ER overload response / Notch-HLH transcription pathway / B cell lineage commitment / positive regulation of cardiac muscle cell apoptotic process / thymocyte apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / positive regulation of execution phase of apoptosis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / Zygotic genome activation (ZGA) / necroptotic process / positive regulation of release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / rRNA transcription / mitophagy / SUMOylation of transcription factors / negative regulation of telomere maintenance via telomerase / histone deacetylase complex / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / Transcriptional Regulation by VENTX / DNA damage response, signal transduction by p53 class mediator / response to X-ray / replicative senescence / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / neuroblast proliferation / cellular response to UV-C / : / hematopoietic stem cell differentiation / negative regulation of reactive oxygen species metabolic process / chromosome organization / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / T cell proliferation involved in immune response / glial cell proliferation / embryonic organ development / positive regulation of RNA polymerase II transcription preinitiation complex assembly / Pyroptosis / cis-regulatory region sequence-specific DNA binding / hematopoietic progenitor cell differentiation / cellular response to glucose starvation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cellular response to actinomycin D / somitogenesis / type II interferon-mediated signaling pathway / negative regulation of stem cell proliferation / core promoter sequence-specific DNA binding
Similarity search - Function
Histone deacetylase / Histone deacetylase domain / Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / Arginase; Chain A / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif ...Histone deacetylase / Histone deacetylase domain / Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / Arginase; Chain A / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily / p53-like transcription factor, DNA-binding / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
: / Cellular tumor antigen p53 / Histone deacetylase 8
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsDi Marco, S. / Vannini, A. / Volpari, C.
CitationJournal: Embo Rep. / Year: 2007
Title: Substrate Binding to Histone Deacetylases as Revealed by Crystal Structure of Hdac8-Substrate Complex
Authors: Vannini, A. / Volpari, C. / Gallinari, P. / Jones, P. / Mattu, M. / Carfi, A. / Defrancesco, R. / Steinkuhler, C. / Di Marco, S.
History
DepositionJul 10, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 4, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Dec 21, 2016Group: Source and taxonomy
Revision 1.3May 29, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc ...exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_biol / struct_conn
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval / _struct_conn.pdbx_leaving_atom_flag
Revision 1.4Dec 13, 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_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: HISTONE DEACETYLASE 8
B: HISTONE DEACETYLASE 8
G: GLYCYL-GLYCYL-GLYCINE
I: PEPTIDIC SUBSTRATE
L: PEPTIDIC SUBSTRATE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,46811
Polymers88,1815
Non-polymers2876
Water13,439746
1
A: HISTONE DEACETYLASE 8
I: PEPTIDIC SUBSTRATE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1405
Polymers43,9962
Non-polymers1443
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-3.5 kcal/mol
Surface area17810 Å2
MethodPQS
2
B: HISTONE DEACETYLASE 8
G: GLYCYL-GLYCYL-GLYCINE
L: PEPTIDIC SUBSTRATE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3296
Polymers44,1853
Non-polymers1443
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1760 Å2
ΔGint-5.2 kcal/mol
Surface area18100 Å2
MethodPQS
Unit cell
Length a, b, c (Å)52.304, 151.801, 57.552
Angle α, β, γ (deg.)90.00, 117.02, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-1, 0.00146, 0.00018), (-0.00146, -1, -0.00089), (0.00018, -0.00089, 1)
Vector: 15.7454, -32.11587, -0.00971)

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein HISTONE DEACETYLASE 8 / HDAC8 / HD8


Mass: 43158.941 Da / Num. of mol.: 2 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET21B / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: Q9BY41

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Protein/peptide , 2 types, 3 molecules GIL

#2: Protein/peptide GLYCYL-GLYCYL-GLYCINE


Mass: 189.171 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others)
#3: Protein/peptide PEPTIDIC SUBSTRATE


Mass: 836.980 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others) / References: UniProt: P04637*PLUS

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Non-polymers , 3 types, 752 molecules

#4: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 746 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsENGINEERED RESIDUE IN CHAIN A, TYR 306 TO PHE ENGINEERED RESIDUE IN CHAIN B, TYR 306 TO PHE
Sequence detailsY306 MUTATED TO F306. IEGRSHHHHHH ADDED AT THE C-TERMINUS

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.21 Å3/Da / Density % sol: 43.95 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop
Details: HDAC8 POINT MUTANT Y306F, IN 50 MM TRIS-HCL PH 8.0, 5% GLYCEROL, 1 MM DTT, 150 MM KCL, WAS CONCENTRATED TO 217 UM, RESPECTIVELY. Y306F-HDAC8 PLUS 15 MOLAR EXCESSES OF SUBSTRATE, WAS ...Details: HDAC8 POINT MUTANT Y306F, IN 50 MM TRIS-HCL PH 8.0, 5% GLYCEROL, 1 MM DTT, 150 MM KCL, WAS CONCENTRATED TO 217 UM, RESPECTIVELY. Y306F-HDAC8 PLUS 15 MOLAR EXCESSES OF SUBSTRATE, WAS CRYSTALLIZED AT RT BY THE HANGING-DROP METHOD IN 50 MM TRIS-HCL PH 8.0, 50 MM MGCL2, 10% PEG 4,000, 2 MM TRI(2-CARBOXYETHYL)PHOSPHIN (TCEP) AND 30 MM GLYCYL-GLYCYL- GLYCINE.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.931
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.931 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 53718 / % possible obs: 95.6 % / Observed criterion σ(I): 3 / Redundancy: 4.8 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 18.2
Reflection shellResolution: 2→2.06 Å / Redundancy: 2 % / Rmerge(I) obs: 0.15 / Mean I/σ(I) obs: 6.1 / % possible all: 59.4

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1W22

1w22


Resolution: 2→50 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.915 / SU B: 4.232 / SU ML: 0.12 / Cross valid method: THROUGHOUT / ESU R: 0.192 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23 2651 5.1 %RANDOM
Rwork0.176 ---
obs0.179 49636 97.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 18.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å20 Å20.3 Å2
2--0.25 Å20 Å2
3---0.09 Å2
Refinement stepCycle: LAST / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5819 0 6 746 6571
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0215970
X-RAY DIFFRACTIONr_bond_other_d0.0020.025309
X-RAY DIFFRACTIONr_angle_refined_deg1.4331.9618080
X-RAY DIFFRACTIONr_angle_other_deg0.914312374
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3615738
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.090.2871
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.026660
X-RAY DIFFRACTIONr_gen_planes_other0.0060.021218
X-RAY DIFFRACTIONr_nbd_refined0.2350.21410
X-RAY DIFFRACTIONr_nbd_other0.2410.26283
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.1030.23305
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1770.2517
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1760.217
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2910.237
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2590.234
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6471.53680
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.18825913
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.07132290
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.394.52167
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: 2→2.05 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.276 158
Rwork0.199 2690

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