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

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Basic information

Entry
Database: PDB / ID: 4cby
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 / 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-KEE / Histone deacetylase 4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.72 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 17, 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
D: HISTONE DEACETYLASE 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,01124
Polymers171,0224
Non-polymers1,98920
Water1,63991
1
A: HISTONE DEACETYLASE 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2536
Polymers42,7561
Non-polymers4975
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: HISTONE DEACETYLASE 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2536
Polymers42,7561
Non-polymers4975
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
3
C: HISTONE DEACETYLASE 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2536
Polymers42,7561
Non-polymers4975
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
4
D: HISTONE DEACETYLASE 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2536
Polymers42,7561
Non-polymers4975
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)54.151, 161.816, 83.732
Angle α, β, γ (deg.)90.00, 97.03, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
HISTONE DEACETYLASE 4 / / HD4 / HDAC4


Mass: 42755.559 Da / Num. of mol.: 4 / Fragment: CATALYTIC DOMAIN, RESIDUES 648-1033 / Mutation: YES
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-KEE / (1R,2R,3R)-2-[4-(1,3-oxazol-5-yl)phenyl]-N-oxidanyl-3-phenyl-cyclopropane-1-carboxamide


Mass: 320.342 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H16N2O3
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 91 / 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: 2.13 Å3/Da / Density % sol: 42.22 % / Description: NONE
Crystal growpH: 6.5
Details: 18-24% (W/V) PEG 3350, 0.2 M NACL AND 100 MM BIS-TRIS PH 5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.72→29.4 Å / Num. obs: 37697 / % possible obs: 98.4 % / Observed criterion σ(I): 2 / Redundancy: 3.7 % / Biso Wilson estimate: 51.1 Å2 / Rmerge(I) obs: 0.16 / Net I/σ(I): 6.9
Reflection shellResolution: 2.72→2.87 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.66 / Mean I/σ(I) obs: 1.9 / % possible all: 90.1

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.72→83.1 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.908 / Cross valid method: THROUGHOUT / ESU R Free: 0.387 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24592 1886 5 %RANDOM
Rwork0.20907 ---
obs0.21096 35785 98.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.257 Å2
Baniso -1Baniso -2Baniso -3
1--2.2 Å20 Å20.27 Å2
2---2.75 Å20 Å2
3---5.02 Å2
Refinement stepCycle: LAST / Resolution: 2.72→83.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11232 0 112 91 11435
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.01911656
X-RAY DIFFRACTIONr_bond_other_d00.027559
X-RAY DIFFRACTIONr_angle_refined_deg1.4211.96515793
X-RAY DIFFRACTIONr_angle_other_deg4.5643.00118453
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.71551519
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.54824.04453
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.828151731
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6271551
X-RAY DIFFRACTIONr_chiral_restr0.0760.21779
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.02113217
X-RAY DIFFRACTIONr_gen_planes_other0.0370.022354
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 2.722→2.792 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.372 107 -
Rwork0.331 2170 -
obs--80.57 %

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