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- PDB-6oda: Crystal structure of HDAC8 in complex with compound 2 -

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Basic information

Entry
Database: PDB / ID: 6oda
TitleCrystal structure of HDAC8 in complex with compound 2
ComponentsHistone deacetylase 8
KeywordsHYDROLASE / histone deacetylase / HDAC8 / hydroxamic acid
Function / homology
Function and homology information


histone decrotonylase activity / histone deacetylase / protein lysine deacetylase activity / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / regulation of telomere maintenance / 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 / Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides / regulation of telomere maintenance / 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 / epigenetic regulation of gene expression / 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 / nucleus / metal ion binding / 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-C7 / : / Histone deacetylase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.88 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: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms / struct_conn
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

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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)139,41515
Polymers137,9283
Non-polymers1,48812
Water543
1
A: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4725
Polymers45,9761
Non-polymers4964
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4725
Polymers45,9761
Non-polymers4964
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4725
Polymers45,9761
Non-polymers4964
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.750, 91.290, 92.700
Angle α, β, γ (deg.)90.00, 94.09, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#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
#2: Chemical ChemComp-C7 / N-{2-[3-(hydroxyamino)-3-oxopropyl]phenyl}-3-(trifluoromethyl)benzamide


Mass: 352.308 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C17H15F3N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 39.098 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: K
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 2.69 Å3/Da / Density % sol: 54.19 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.3
Details: 0.1M MES pH5.3, 5% PEG6000, 0.06M Gly-Gly-Gly, 4mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.993 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 3, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.993 Å / Relative weight: 1
ReflectionResolution: 2.88→50 Å / Num. obs: 29616 / % possible obs: 99.8 % / Redundancy: 3.79 % / Rmerge(I) obs: 0.112 / Net I/σ(I): 10.9
Reflection shellResolution: 2.88→2.95 Å / Redundancy: 3.83 % / Num. unique obs: 1892 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1T64

1t64


Resolution: 2.88→50 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.885 / SU B: 37.587 / SU ML: 0.326 / Cross valid method: THROUGHOUT / ESU R Free: 0.399 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24875 1521 4.9 %RANDOM
Rwork0.1988 ---
obs0.20129 29616 93.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 56.341 Å2
Baniso -1Baniso -2Baniso -3
1-0.22 Å2-0 Å21.53 Å2
2--0.57 Å2-0 Å2
3----1 Å2
Refinement stepCycle: 1 / Resolution: 2.88→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8411 0 84 3 8498
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0198723
X-RAY DIFFRACTIONr_bond_other_d0.0010.027919
X-RAY DIFFRACTIONr_angle_refined_deg1.2371.96311823
X-RAY DIFFRACTIONr_angle_other_deg0.911318389
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.09551076
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.96724.155373
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.523151415
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.9481533
X-RAY DIFFRACTIONr_chiral_restr0.0650.21292
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219669
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021780
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_it0.8534.0854316
X-RAY DIFFRACTIONr_mcbond_other0.8524.0854315
X-RAY DIFFRACTIONr_mcangle_it1.546.1255388
X-RAY DIFFRACTIONr_mcangle_other1.546.1265389
X-RAY DIFFRACTIONr_scbond_it1.0564.2664407
X-RAY DIFFRACTIONr_scbond_other1.0524.264403
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.5746.3576430
X-RAY DIFFRACTIONr_long_range_B_refined4.70549.20310107
X-RAY DIFFRACTIONr_long_range_B_other4.70649.21310108
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.88→2.955 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 107 -
Rwork0.317 1892 -
obs--82.64 %
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)
11.1656-0.3110.01430.57810.1321.0733-0.06230.0975-0.01460.0692-0.0711-0.0444-0.0787-0.02030.13350.15220.0355-0.10780.0449-0.00170.125196.70828.3648-53.3058
21.8218-0.03220.35760.9801-0.02230.64550.18710.21790.05980.0156-0.0768-0.33440.0849-0.0847-0.11030.02480.012-0.02390.06340.0380.2982129.1399-19.1168-54.8019
31.7780.2420.69130.63720.5471.7336-0.2101-0.1396-0.0401-0.1555-0.06920.0393-0.0853-0.02130.27930.17610.0642-0.06410.0728-0.0380.143689.2309-9.6104-99.226
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A14 - 377
2X-RAY DIFFRACTION2B14 - 376
3X-RAY DIFFRACTION3C14 - 376

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