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- PDB-4cbt: Design, synthesis, and biological evaluation of potent and select... -

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Basic information

Entry
Database: PDB / ID: 4cbt
TitleDesign, synthesis, and biological evaluation of potent and selective Class IIa HDAC inhibitors as a potential therapy for Huntington's disease
ComponentsHISTONE DEACETYLASE 4
KeywordsHYDROLASE / NEURODEGENERATION / HUNTINGTONS DISEASE / AMYOTROPHIC LATERAL SCLEROSIS / MUSCLE ATROPHY / CLASS IIA HISTONE DEACETYLASE INHIBITORS / SAR / HYDROXAMIC ACID / CYCLOPROPANATION
Function / homology
Function and homology information


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 / regulation of protein binding / protein deacetylation / cardiac muscle hypertrophy in response to stress / histone deacetylase ...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 / regulation of protein binding / protein deacetylation / cardiac muscle hypertrophy in response to stress / histone deacetylase / protein lysine deacetylase activity / negative regulation of glycolytic process / SUMO transferase activity / histone deacetylase activity / negative regulation of gene expression, epigenetic / B cell activation / type I interferon-mediated signaling pathway / Notch-HLH transcription pathway / potassium ion binding / protein sumoylation / histone deacetylase complex / RUNX3 regulates p14-ARF / transcription repressor complex / SUMOylation of chromatin organization proteins / response to interleukin-1 / B cell differentiation / SUMOylation of intracellular receptors / negative regulation of DNA-binding transcription factor activity / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / histone deacetylase binding / positive regulation of DNA-binding transcription factor activity / nervous system development / DNA-binding transcription factor binding / RNA polymerase II-specific DNA-binding transcription factor binding / molecular adaptor activity / 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-9F4 / Histone deacetylase 4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.03 Å
AuthorsBurli, R.W. / Luckhurst, C.A. / Aziz, O. / Matthews, K.L. / Yates, D. / Lyons, K.A. / Beconi, M. / McAllister, G. / Breccia, P. / Stott, A.J. ...Burli, R.W. / Luckhurst, C.A. / Aziz, O. / Matthews, K.L. / Yates, D. / Lyons, K.A. / Beconi, M. / McAllister, G. / Breccia, P. / Stott, A.J. / Penrose, S.D. / Wall, M. / Lamers, M. / Leonard, P. / Mueller, I. / Richardson, C.M. / Jarvis, R. / Stones, L. / Hughes, S. / Wishart, G. / Haughan, A.F. / O'Connell, C. / Mead, T. / McNeil, H. / Vann, J. / Mangette, J. / Maillard, M. / Beaumont, V. / Munoz-Sanjuan, I. / Dominguez, C.
CitationJournal: J. Med. Chem. / Year: 2013
Title: Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease.
Authors: Burli, R.W. / Luckhurst, C.A. / Aziz, O. / Matthews, K.L. / Yates, D. / Lyons, K.A. / Beconi, M. / McAllister, G. / Breccia, P. / Stott, A.J. / Penrose, S.D. / Wall, M. / Lamers, M. / ...Authors: Burli, R.W. / Luckhurst, C.A. / Aziz, O. / Matthews, K.L. / Yates, D. / Lyons, K.A. / Beconi, M. / McAllister, G. / Breccia, P. / Stott, A.J. / Penrose, S.D. / Wall, M. / Lamers, M. / Leonard, P. / Muller, I. / Richardson, C.M. / Jarvis, R. / Stones, L. / Hughes, S. / Wishart, G. / Haughan, A.F. / O'Connell, C. / Mead, T. / McNeil, H. / Vann, J. / Mangette, J. / Maillard, M. / Beaumont, V. / Munoz-Sanjuan, I. / Dominguez, C.
History
DepositionOct 16, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 11, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2014Group: Database references
Revision 1.2Feb 7, 2018Group: Database references / Structure summary
Category: audit_author / citation ...audit_author / citation / citation_author / struct
Item: _audit_author.name / _citation.journal_abbrev ..._audit_author.name / _citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name / _struct.title

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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)129,83312
Polymers128,3933
Non-polymers1,4419
Water18010
1
A: HISTONE DEACETYLASE 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2784
Polymers42,7981
Non-polymers4803
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: HISTONE DEACETYLASE 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2784
Polymers42,7981
Non-polymers4803
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: HISTONE DEACETYLASE 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2784
Polymers42,7981
Non-polymers4803
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)104.410, 104.410, 88.440
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 / HDAC4


Mass: 42797.637 Da / Num. of mol.: 3 / Fragment: CATALYTIC DOMAIN, RESIDUES 648-1033
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56524, histone deacetylase
#2: Chemical ChemComp-9F4 / (1R,2R,3R)-2-[4-(5-fluoranylpyrimidin-2-yl)phenyl]-N-oxidanyl-3-phenyl-cyclopropane-1-carboxamide


Mass: 349.358 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C20H16FN3O2
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 2.17 Å3/Da / Density % sol: 43.26 % / Description: NONE
Crystal growpH: 6.5 / Details: 0.1 M BISTRIS PH 6.5, 22% PEG MME 5000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9173
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9173 Å / Relative weight: 1
ReflectionResolution: 3.03→90.42 Å / Num. obs: 20882 / % possible obs: 99.8 % / Observed criterion σ(I): 2 / Redundancy: 5.3 % / Rmerge(I) obs: 0.16 / Net I/σ(I): 8.5
Reflection shellResolution: 3.03→3.11 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.68 / Mean I/σ(I) obs: 2.5 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.5.0110refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.03→90.42 Å / Cor.coef. Fo:Fc: 0.908 / Cor.coef. Fo:Fc free: 0.848 / Cross valid method: THROUGHOUT / ESU R Free: 0.536 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.27335 1070 5.1 %RANDOM
Rwork0.21139 ---
obs0.21452 19793 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.7 Å2
Baniso -1Baniso -2Baniso -3
1-1.95 Å20.98 Å20 Å2
2--1.95 Å20 Å2
3----2.93 Å2
Refinement stepCycle: LAST / Resolution: 3.03→90.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7899 0 84 10 7993
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0218192
X-RAY DIFFRACTIONr_bond_other_d00.025404
X-RAY DIFFRACTIONr_angle_refined_deg1.1831.9611096
X-RAY DIFFRACTIONr_angle_other_deg4.4753.00113127
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.07651036
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.7523.602347
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.742151242
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.3921547
X-RAY DIFFRACTIONr_chiral_restr0.260.21225
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0219235
X-RAY DIFFRACTIONr_gen_planes_other0.0310.021695
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_it0.1921.55169
X-RAY DIFFRACTIONr_mcbond_other01.52149
X-RAY DIFFRACTIONr_mcangle_it0.35528247
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.31133023
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.4894.52840
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: 3.032→3.111 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.356 82 -
Rwork0.252 1492 -
obs--100 %

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