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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 H4K16 deacetylase activity, hydrolytic mechanism / histone H4K5 deacetylase activity, hydrolytic mechanism / histone H4K8 deacetylase activity, hydrolytic mechanism / histone H3K4 deacetylase activity, hydrolytic mechanism / histone H3K14 deacetylase activity, hydrolytic mechanism / histone H4K12 deacetylase activity, hydrolytic mechanism / histone deacetylase / histone H3K9 deacetylase activity, hydrolytic mechanism / Loss of function of TP53 in cancer due to loss of tetramerization ability ...histone decrotonylase activity / histone H4K16 deacetylase activity, hydrolytic mechanism / histone H4K5 deacetylase activity, hydrolytic mechanism / histone H4K8 deacetylase activity, hydrolytic mechanism / histone H3K4 deacetylase activity, hydrolytic mechanism / histone H3K14 deacetylase activity, hydrolytic mechanism / histone H4K12 deacetylase activity, hydrolytic mechanism / histone deacetylase / histone H3K9 deacetylase activity, hydrolytic mechanism / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / negative regulation of helicase activity / 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 / regulation of fibroblast apoptotic process / intrinsic apoptotic signaling pathway in response to hypoxia / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / glucose catabolic process to lactate via pyruvate / positive regulation of mitochondrial membrane permeability / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / regulation of telomere maintenance / protein lysine deacetylase activity / 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 / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase regulator activity / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / mitotic sister chromatid cohesion / T cell lineage commitment / mitochondrial DNA repair / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / histone deacetylase activity / nuclear chromosome / ER overload response / B cell lineage commitment / thymocyte apoptotic process / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of mitophagy / Notch-HLH transcription pathway / cardiac septum morphogenesis / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / negative regulation of telomere maintenance via telomerase / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / rRNA transcription / TFIID-class transcription factor complex binding / SUMOylation of transcription factors / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / intrinsic apoptotic signaling pathway by p53 class mediator / T cell proliferation involved in immune response / negative regulation of reactive oxygen species metabolic process / positive regulation of execution phase of apoptosis / histone deacetylase complex / Transcriptional Regulation by VENTX / replicative senescence / cellular response to UV-C / general transcription initiation factor binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to actinomycin D / neuroblast proliferation / positive regulation of RNA polymerase II transcription preinitiation complex assembly / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / response to X-ray / type II interferon-mediated signaling pathway / hematopoietic stem cell differentiation / Pyroptosis / chromosome organization / viral process / embryonic organ development / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / glial cell proliferation / hematopoietic progenitor cell differentiation / 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 / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain ...Histone deacetylase / Histone deacetylase domain / 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 / Arginase; Chain A / 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
Revision 1.5Oct 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: 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
Has protein modificationY
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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