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- PDB-2v5x: Crystal structure of HDAC8-inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 2v5x
TitleCrystal structure of HDAC8-inhibitor complex
ComponentsHISTONE DEACETYLASE 8
KeywordsHYDROLASE / HYDROXAMATE INHIBITOR / CHROMATIN REGULATOR / HISTONE DEACETYLASE / P53 / HDAC / HDAC8 / NUCLEUS / REPRESSOR / CHROMATIN / DRUG DESIGN / DEACETYLATION / TRANSCRIPTION / TRANSCRIPTION REGULATION / NUCLEAR PROTEIN / PEPTIDIC SUBSTRATE
Function / homology
Function and homology information


histone decrotonylase activity / histone deacetylase activity, hydrolytic mechanism / histone deacetylase / regulation of telomere maintenance / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / mitotic sister chromatid cohesion / histone deacetylase activity / nuclear chromosome / Notch-HLH transcription pathway ...histone decrotonylase activity / histone deacetylase activity, hydrolytic mechanism / histone deacetylase / regulation of telomere maintenance / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / mitotic sister chromatid cohesion / histone deacetylase activity / nuclear chromosome / Notch-HLH transcription pathway / histone deacetylase complex / negative regulation of protein ubiquitination / Hsp70 protein binding / Resolution of Sister Chromatid Cohesion / HDACs deacetylate histones / Hsp90 protein binding / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / regulation of protein stability / Separation of Sister Chromatids / heterochromatin formation / chromatin organization / DNA-binding transcription factor binding / negative regulation of transcription by RNA polymerase II / nucleoplasm / metal ion binding / nucleus / cytoplasm
Similarity search - Function
Histone deacetylase / Histone deacetylase domain / Arginase; Chain A / : / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
: / Chem-V5X / Histone deacetylase 8
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsDi Marco, S. / Vannini, A. / Volpari, C. / Gallinari, P. / Jones, P. / Mattu, M. / Carfi, A. / Defrancesco, R. / Steinkuhler, 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 1.1Sep 12, 2012Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Other / Source and taxonomy / Structure summary / Version format compliance
Revision 1.2May 29, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc ...exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_biol
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.3Dec 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_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_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_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.pdbx_dist_value / _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_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

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Assembly

Deposited unit
A: HISTONE DEACETYLASE 8
B: HISTONE DEACETYLASE 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,94110
Polymers86,4062
Non-polymers1,5358
Water5,783321
1
A: HISTONE DEACETYLASE 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9705
Polymers43,2031
Non-polymers7674
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: HISTONE DEACETYLASE 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9705
Polymers43,2031
Non-polymers7674
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)84.298, 98.694, 110.474
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein HISTONE DEACETYLASE 8 / HDAC8 / HD8


Mass: 43202.949 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
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#4: Chemical ChemComp-V5X / (2R)-N~8~-HYDROXY-2-{[(5-METHOXY-2-METHYL-1H-INDOL-3-YL)ACETYL]AMINO}-N~1~-[2-(2-PHENYL-1H-INDOL-3-YL)ETHYL]OCTANEDIAMIDE


Mass: 623.741 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H41N5O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 321 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, SER 39 TO ASP ENGINEERED RESIDUE IN CHAIN B, SER 39 TO ASP
Sequence detailsS39 MUTATED TO D39. IEGRSHHHHHH ADDED AT THE C-TERMINUS

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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: 2.72 Å3/Da / Density % sol: 54.4 % / 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: 2.25→74.53 Å / Num. obs: 44426 / % possible obs: 98.7 % / Observed criterion σ(I): 2 / Redundancy: 6.3 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 16.8
Reflection shellResolution: 2.25→2.37 Å / Redundancy: 6.2 % / Rmerge(I) obs: 0.6 / Mean I/σ(I) obs: 3.1 / % possible all: 98.1

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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: 2.25→50 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.924 / SU B: 6.683 / SU ML: 0.16 / Cross valid method: THROUGHOUT / ESU R: 0.266 / ESU R Free: 0.211 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24 2203 5 %RANDOM
Rwork0.196 ---
obs0.198 41545 98.5 %-
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: 35.83 Å2
Baniso -1Baniso -2Baniso -3
1-0.31 Å20 Å20 Å2
2---3.53 Å20 Å2
3---3.22 Å2
Refinement stepCycle: LAST / Resolution: 2.25→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5613 0 98 321 6032
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0215858
X-RAY DIFFRACTIONr_bond_other_d0.0020.025157
X-RAY DIFFRACTIONr_angle_refined_deg1.421.9697944
X-RAY DIFFRACTIONr_angle_other_deg1.0013.00112027
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4675716
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_restr0.0880.2855
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.026505
X-RAY DIFFRACTIONr_gen_planes_other0.0050.021169
X-RAY DIFFRACTIONr_nbd_refined0.2270.21409
X-RAY DIFFRACTIONr_nbd_other0.2350.26269
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0880.23276
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.150.2247
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3310.211
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2250.246
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2560.29
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6581.53573
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.26125753
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.7532285
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.9794.52191
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: 2.25→2.31 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.31 177
Rwork0.27 2993

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