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- PDB-6hsk: Crystal structure of a human HDAC8 L6 loop mutant complexed with ... -

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Basic information

Entry
Database: PDB / ID: 6hsk
TitleCrystal structure of a human HDAC8 L6 loop mutant complexed with Quisinostat
ComponentsHistone deacetylase 8
KeywordsHYDROLASE / Epigenetics / Histone deacetylase / HDAC8 / Selective inhibitor
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 / 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-GOK / : / Histone deacetylase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.096 Å
AuthorsMarek, M. / Shaik, T.B. / Ramos-Morales, E. / Romier, C.
Funding support France, 2items
OrganizationGrant numberCountry
European Commission241865 France
European Commission602080 France
CitationJournal: J. Med. Chem. / Year: 2018
Title: Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
Authors: Marek, M. / Shaik, T.B. / Heimburg, T. / Chakrabarti, A. / Lancelot, J. / Ramos-Morales, E. / Da Veiga, C. / Kalinin, D. / Melesina, J. / Robaa, D. / Schmidtkunz, K. / Suzuki, T. / Holl, R. ...Authors: Marek, M. / Shaik, T.B. / Heimburg, T. / Chakrabarti, A. / Lancelot, J. / Ramos-Morales, E. / Da Veiga, C. / Kalinin, D. / Melesina, J. / Robaa, D. / Schmidtkunz, K. / Suzuki, T. / Holl, R. / Ennifar, E. / Pierce, R.J. / Jung, M. / Sippl, W. / Romier, C.
History
DepositionOct 1, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 31, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 7, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 14, 2018Group: Data collection / Structure summary / Category: struct / Item: _struct.title
Revision 1.3Nov 28, 2018Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.4Jan 24, 2024Group: 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,30210
Polymers84,2262
Non-polymers1,0768
Water8,305461
1
A: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6515
Polymers42,1131
Non-polymers5384
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone deacetylase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6515
Polymers42,1131
Non-polymers5384
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)106.390, 106.390, 82.030
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number145
Space group name H-MP32

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Components

#1: Protein Histone deacetylase 8 / HD8


Mass: 42112.766 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Human HDAC8 with loop L6 (AGDPMCS) replaced by human HDAC1 loop L6 (SGDRLGC)
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC8, HDACL1, CDA07 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9BY41, histone deacetylase
#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-GOK / 2-[4-[[(1-methylindol-3-yl)methylamino]methyl]piperidin-1-yl]-~{N}-oxidanyl-pyrimidine-5-carboxamide


Mass: 394.470 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H26N6O2 / Comment: antineoplastic, inhibitor*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 461 / 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: 3.13 Å3/Da / Density % sol: 60.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Bis Tris Propane pH 7.5, 0.2 M NaNO3, 17-21% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 15, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.096→46.08 Å / Num. obs: 60783 / % possible obs: 99.71 % / Redundancy: 5.8 % / CC1/2: 0.991 / Rmerge(I) obs: 0.1598 / Net I/σ(I): 7.27
Reflection shellResolution: 2.096→2.171 Å / Redundancy: 5.5 % / Rmerge(I) obs: 1.213 / Mean I/σ(I) obs: 1.08 / Num. unique obs: 6011 / CC1/2: 0.484 / % possible all: 97.52

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1T67

1t67


Resolution: 2.096→37.47 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.93 / Phase error: 19.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.189 3039 5 %
Rwork0.152 --
obs0.1538 60780 99.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.096→37.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5684 0 64 461 6209
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0085902
X-RAY DIFFRACTIONf_angle_d0.8688012
X-RAY DIFFRACTIONf_dihedral_angle_d16.3263506
X-RAY DIFFRACTIONf_chiral_restr0.054869
X-RAY DIFFRACTIONf_plane_restr0.0051068
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0957-2.12840.33741300.29622476X-RAY DIFFRACTION93
2.1284-2.16330.32431380.26862625X-RAY DIFFRACTION100
2.1633-2.20060.31971390.25232632X-RAY DIFFRACTION100
2.2006-2.24070.2651380.23772625X-RAY DIFFRACTION100
2.2407-2.28370.25361380.21732624X-RAY DIFFRACTION100
2.2837-2.33040.25781390.20272636X-RAY DIFFRACTION100
2.3304-2.3810.25021380.19452621X-RAY DIFFRACTION100
2.381-2.43640.20991390.18042635X-RAY DIFFRACTION100
2.4364-2.49730.25181390.18262641X-RAY DIFFRACTION100
2.4973-2.56480.22751380.17552622X-RAY DIFFRACTION100
2.5648-2.64030.21741390.15992638X-RAY DIFFRACTION100
2.6403-2.72550.20121380.15842634X-RAY DIFFRACTION100
2.7255-2.82280.21871390.15592627X-RAY DIFFRACTION100
2.8228-2.93580.20431380.15752645X-RAY DIFFRACTION100
2.9358-3.06940.19011380.14822633X-RAY DIFFRACTION100
3.0694-3.23110.21661400.15652643X-RAY DIFFRACTION100
3.2311-3.43340.17451390.14072653X-RAY DIFFRACTION100
3.4334-3.69830.15941380.13122607X-RAY DIFFRACTION100
3.6983-4.07010.15281390.12162657X-RAY DIFFRACTION100
4.0701-4.65810.1451390.11132623X-RAY DIFFRACTION100
4.6581-5.86510.15231380.13552626X-RAY DIFFRACTION100
5.8651-37.47610.14371380.13222618X-RAY DIFFRACTION100
Refinement TLS params.

S33: -0 Å ° / 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 °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3353-0.21410.27820.7652-0.02270.5796-0.0339-0.0909-0.02090.06150.0445-0.0204-0.0637-0.07910.23590.0242-0.00830.25230.00470.2119-16.071610.6717-1.296
20.859-0.31170.27310.6303-0.21260.6731-0.0038-0.05340.016-0.0586-0.028-0.0956-0.00690.0070.17680.03670.01060.22640.00160.1946-34.369227.4284-39.4361
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A
2X-RAY DIFFRACTION2chain B

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