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- PDB-6fyz: Development and characterization of a CNS-penetrant benzhydryl hy... -

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Basic information

Entry
Database: PDB / ID: 6fyz
TitleDevelopment and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor
ComponentsHistone deacetylase 4
KeywordsHYDROLASE / Hydroxamic acid / CNS-penetrant / HDAC4 inhibition / Class IIa HDAC inhibitor
Function / homology
Function and homology information


regulation of protein binding / RUNX2 regulates chondrocyte maturation / response to denervation involved in regulation of muscle adaptation / negative regulation of myotube differentiation / peptidyl-lysine deacetylation / positive regulation of protein sumoylation / negative regulation of transcription by competitive promoter binding / histone H4K16 deacetylase activity, hydrolytic mechanism / histone H4K5 deacetylase activity, hydrolytic mechanism / histone H4K8 deacetylase activity, hydrolytic mechanism ...regulation of protein binding / RUNX2 regulates chondrocyte maturation / response to denervation involved in regulation of muscle adaptation / negative regulation of myotube differentiation / peptidyl-lysine deacetylation / positive regulation of protein sumoylation / negative regulation of transcription by competitive promoter binding / 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 / protein deacetylation / histone deacetylase / histone H3K9 deacetylase activity, hydrolytic mechanism / cardiac muscle hypertrophy in response to stress / negative regulation of glycolytic process / SUMO transferase activity / protein lysine deacetylase activity / type I interferon-mediated signaling pathway / histone deacetylase activity / Notch-HLH transcription pathway / negative regulation of gene expression, epigenetic / potassium ion binding / B cell activation / protein sumoylation / histone deacetylase complex / RUNX3 regulates p14-ARF / transcription repressor complex / response to interleukin-1 / B cell differentiation / SUMOylation of chromatin organization proteins / positive regulation of DNA-binding transcription factor activity / epigenetic regulation of gene expression / negative regulation of DNA-binding transcription factor activity / SUMOylation of intracellular receptors / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / nervous system development / DNA-binding transcription factor binding / molecular adaptor activity / RNA polymerase II-specific DNA-binding transcription factor binding / nuclear speck / chromatin remodeling / inflammatory response / RNA polymerase II cis-regulatory region sequence-specific DNA binding / positive regulation of cell population proliferation / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Histone deacetylase, glutamine rich N-terminal domain / Glutamine rich N terminal domain of histone deacetylase 4 / : / Histone deacetylase domain / Arginase; Chain A / Histone deacetylase family / Histone deacetylase domain / Histone deacetylase domain superfamily / Histone deacetylase domain / Ureohydrolase domain superfamily ...Histone deacetylase, glutamine rich N-terminal domain / Glutamine rich N terminal domain of histone deacetylase 4 / : / 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-EBE / Histone deacetylase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsLuckhurst, C.A. / Maillard, M.C. / Dominguez, C.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2019
Title: Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor.
Authors: Luckhurst, C.A. / Aziz, O. / Beaumont, V. / Burli, R.W. / Breccia, P. / Maillard, M.C. / Haughan, A.F. / Lamers, M. / Leonard, P. / Matthews, K.L. / Raphy, G. / Stott, A.J. / Munoz-Sanjuan, ...Authors: Luckhurst, C.A. / Aziz, O. / Beaumont, V. / Burli, R.W. / Breccia, P. / Maillard, M.C. / Haughan, A.F. / Lamers, M. / Leonard, P. / Matthews, K.L. / Raphy, G. / Stott, A.J. / Munoz-Sanjuan, I. / Thomas, B. / Wall, M. / Wishart, G. / Yates, D. / Dominguez, C.
History
DepositionMar 13, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 5, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 26, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Jan 17, 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 4
B: Histone deacetylase 4
C: Histone deacetylase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,86615
Polymers128,3933
Non-polymers1,47312
Water4,143230
1
A: Histone deacetylase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2895
Polymers42,7981
Non-polymers4914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone deacetylase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2895
Polymers42,7981
Non-polymers4914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Histone deacetylase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2895
Polymers42,7981
Non-polymers4914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)105.530, 105.530, 88.860
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 4 / HD4


Mass: 42797.637 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HDAC4, KIAA0288 / Production host: Escherichia coli (E. coli) / References: UniProt: P56524, histone deacetylase
#2: Chemical ChemComp-EBE / (2~{S})-2-(2-fluorophenyl)-2-[4-(2-methylpyrimidin-5-yl)phenyl]-~{N}-oxidanyl-ethanamide


Mass: 337.348 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C19H16FN3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 230 / 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: 2.22 Å3/Da / Density % sol: 44.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M BisTris, 18 to 24% PEG MME 5000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9173 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 11, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9173 Å / Relative weight: 1
ReflectionResolution: 2.15→45.7 Å / Num. obs: 59433 / % possible obs: 98.7 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.14 / Net I/σ(I): 7.7
Reflection shellResolution: 2.15→2.206 Å / Rmerge(I) obs: 0.574 / Mean I/σ(I) obs: 2.5 / % possible all: 97.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
iMOSFLMdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3c0y

3c0y


Resolution: 2.15→45.7 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.929 / SU B: 5.658 / SU ML: 0.143 / Cross valid method: THROUGHOUT / ESU R: 0.252 / ESU R Free: 0.192 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2284 3018 5.1 %RANDOM
Rwork0.19264 ---
obs0.19447 56390 98.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 28.716 Å2
Baniso -1Baniso -2Baniso -3
1-0.17 Å20.09 Å20 Å2
2--0.17 Å2-0 Å2
3----0.56 Å2
Refinement stepCycle: 1 / Resolution: 2.15→45.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7942 0 84 230 8256
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0198207
X-RAY DIFFRACTIONr_bond_other_d0.0020.027381
X-RAY DIFFRACTIONr_angle_refined_deg1.2681.95411135
X-RAY DIFFRACTIONr_angle_other_deg0.954317078
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.07651048
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.36423.644343
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.844151236
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5371545
X-RAY DIFFRACTIONr_chiral_restr0.070.21232
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219250
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021696
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_it1.2522.884222
X-RAY DIFFRACTIONr_mcbond_other1.2512.884221
X-RAY DIFFRACTIONr_mcangle_it2.1354.3065260
X-RAY DIFFRACTIONr_mcangle_other2.1354.3075261
X-RAY DIFFRACTIONr_scbond_it1.3333.0083985
X-RAY DIFFRACTIONr_scbond_other1.3333.0083986
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.2244.4585876
X-RAY DIFFRACTIONr_long_range_B_refined3.76433.98939
X-RAY DIFFRACTIONr_long_range_B_other3.73133.8668913
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.15→2.206 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.301 223 -
Rwork0.269 4170 -
obs--98.85 %

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