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- PDB-6odc: Crystal structure of HDAC8 in complex with compound 30 -

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Basic information

Entry
Database: PDB / ID: 6odc
TitleCrystal structure of HDAC8 in complex with compound 30
ComponentsHistone deacetylase 8
KeywordsHYDROLASE / histone deacetylase / HDAC8 / hydroxamic acid
Function / homology
Function and homology information


histone decrotonylase activity / histone deacetylase / protein lysine deacetylase activity / regulation of telomere maintenance / 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 ...histone decrotonylase activity / histone deacetylase / protein lysine deacetylase activity / regulation of telomere maintenance / 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 / Resolution of Sister Chromatid Cohesion / Hsp70 protein binding / HDACs deacetylate histones / Hsp90 protein binding / regulation of protein stability / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Separation of Sister Chromatids / 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-M7Y / Histone deacetylase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsZheng, X. / Conti, C. / Caravella, J. / Zablocki, M.-M. / Bair, K. / Barczak, N. / Han, B. / Lancia Jr., D. / Liu, C. / Martin, M. ...Zheng, X. / Conti, C. / Caravella, J. / Zablocki, M.-M. / Bair, K. / Barczak, N. / Han, B. / Lancia Jr., D. / Liu, C. / Martin, M. / Ng, P.Y. / Rudnitskaya, A. / Thomason, J.J. / Garcia-Dancey, R. / Hardy, C. / Lahdenranta, J. / Leng, C. / Li, P. / Pardo, E. / Saldahna, A. / Tan, T. / Toms, A.V. / Yao, L. / Zhang, C.
CitationJournal: To Be Published
Title: Structure-based Discovery of Novel N-(E)-N-Hydroxy-3-(2-(2-oxoimidazolidin-1-yl)phenyl)acrylamides as Potent and Selective HDAC8 inhibitors
Authors: Zheng, X. / Conti, C. / Caravella, J. / Zablocki, M.-M. / Bair, K. / Barczak, N. / Han, B. / Lancia Jr., D. / Liu, C. / Martin, M. / Ng, P.Y. / Rudnitskaya, A. / Thomason, J.J. / Garcia- ...Authors: Zheng, X. / Conti, C. / Caravella, J. / Zablocki, M.-M. / Bair, K. / Barczak, N. / Han, B. / Lancia Jr., D. / Liu, C. / Martin, M. / Ng, P.Y. / Rudnitskaya, A. / Thomason, J.J. / Garcia-Dancey, R. / Hardy, C. / Lahdenranta, J. / Leng, C. / Li, P. / Pardo, E. / Saldahna, A. / Tan, T. / Toms, A.V. / Yao, L. / Zhang, C.
History
DepositionMar 26, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 1, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 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 / struct_conn / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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
C: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,63719
Polymers137,9283
Non-polymers1,70916
Water1,06359
1
A: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6498
Polymers45,9761
Non-polymers6737
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5256
Polymers45,9761
Non-polymers5495
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4635
Polymers45,9761
Non-polymers4874
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.540, 91.161, 92.574
Angle α, β, γ (deg.)90.00, 94.07, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13B
23C

NCS domain segments:

Component-ID: 0 / Beg auth comp-ID: LEU / Beg label comp-ID: LEU / End auth comp-ID: VAL / End label comp-ID: VAL / Refine code: 0 / Auth seq-ID: 14 - 377 / Label seq-ID: 38 - 401

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13BB
23CC

NCS ensembles :
ID
1
2
3

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Components

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Protein , 1 types, 3 molecules ABC

#1: Protein Histone deacetylase 8 / / HD8


Mass: 45975.906 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC8, HDACL1, CDA07 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q9BY41, histone deacetylase

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Non-polymers , 5 types, 75 molecules

#2: Chemical ChemComp-ZN / ZINC ION


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


Mass: 39.098 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: K
#4: Chemical ChemComp-M7Y / (2E)-3-[2-(3-cyclopentyl-5,5-dimethyl-2-oxoimidazolidin-1-yl)phenyl]-N-hydroxyprop-2-enamide


Mass: 343.420 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C19H25N3O3 / Feature type: SUBJECT OF INVESTIGATION
#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.: 59 / 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: 2.67 Å3/Da / Density % sol: 53.96 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.3
Details: 0.1M MES pH5.3, 5% PEG6000, 0.14 M Gly-Gly-Gly, 2mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.99 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 6, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 35823 / % possible obs: 99.8 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.0125 / Net I/σ(I): 14.8
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 3547 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1t64

1t64


Resolution: 2.8→50 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.931 / SU B: 17.127 / SU ML: 0.313 / Cross valid method: THROUGHOUT / ESU R Free: 0.339 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23577 1768 4.9 %RANDOM
Rwork0.1944 ---
obs0.19642 34035 99.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 76.315 Å2
Baniso -1Baniso -2Baniso -3
1-4.14 Å2-0 Å2-3.68 Å2
2---0.92 Å2-0 Å2
3----2.67 Å2
Refinement stepCycle: 1 / Resolution: 2.8→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8476 0 100 59 8635
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0198858
X-RAY DIFFRACTIONr_bond_other_d0.0030.028093
X-RAY DIFFRACTIONr_angle_refined_deg1.4521.96411953
X-RAY DIFFRACTIONr_angle_other_deg0.966318767
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.35451087
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.54624.18378
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.924151436
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.9261533
X-RAY DIFFRACTIONr_chiral_restr0.0780.21297
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219797
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021798
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_it5.1647.5494348
X-RAY DIFFRACTIONr_mcbond_other5.1437.5484347
X-RAY DIFFRACTIONr_mcangle_it7.79211.3175429
X-RAY DIFFRACTIONr_mcangle_other7.79711.3185430
X-RAY DIFFRACTIONr_scbond_it5.1588.014510
X-RAY DIFFRACTIONr_scbond_other5.1578.014511
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.01811.8616523
X-RAY DIFFRACTIONr_long_range_B_refined10.95189.0879941
X-RAY DIFFRACTIONr_long_range_B_other10.95689.0829942
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.07 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A24030
12B24030
21A23076
22C23076
31B23090
32C23090
LS refinement shellResolution: 2.8→2.869 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 123 -
Rwork0.34 2324 -
obs--91.75 %

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