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Yorodumi- PDB-5a2s: Potent, selective and CNS-penetrant tetrasubstituted cyclopropane... -
+Open data
-Basic information
Entry | Database: PDB / ID: 5a2s | ||||||
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Title | Potent, selective and CNS-penetrant tetrasubstituted cyclopropane class IIa histone deacetylase (HDAC) inhibitors | ||||||
Components | HISTONE DEACETYLASE 4 | ||||||
Keywords | HYDROLASE / CLASS IIA HDAC INHIBITORS / HYDROXAMIC ACID / CNS EXPOSURE / TETRASUBSTITUTED CYCLOPROPANE / CYCLOPROPANATION / HUNTINGTON'S DISEASE | ||||||
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 | ||||||
Biological species | HOMO SAPIENS (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å | ||||||
Authors | Luckhurst, C.A. / Breccia, P. / Stott, A.J. / Aziz, O. / Birch, H. / Burli, R.W. / Hughes, S. / Jarvis, R.E. / Lamers, M. / Leonard, P. ...Luckhurst, C.A. / Breccia, P. / Stott, A.J. / Aziz, O. / Birch, H. / Burli, R.W. / Hughes, S. / Jarvis, R.E. / Lamers, M. / Leonard, P. / Matthews, K.L. / McAllister, G. / Pollack, S. / Saville-Stones, E. / Wishart, G. / Yates, D. / Dominguez, C. | ||||||
Citation | Journal: Acs Med.Chem.Lett. / Year: 2016 Title: Potent, Selective, and Cns-Penetrant Tetrasubstituted Cyclopropane Class Iia Histone Deacetylase (Hdac) Inhibitors. Authors: Luckhurst, C.A. / Breccia, P. / Stott, A.J. / Aziz, O. / Birch, H.L. / Burli, R.W. / Hughes, S.J. / Jarvis, R.E. / Lamers, M. / Leonard, P.M. / Matthews, K.L. / Mcallister, G. / Pollack, S. ...Authors: Luckhurst, C.A. / Breccia, P. / Stott, A.J. / Aziz, O. / Birch, H.L. / Burli, R.W. / Hughes, S.J. / Jarvis, R.E. / Lamers, M. / Leonard, P.M. / Matthews, K.L. / Mcallister, G. / Pollack, S. / Saville-Stones, E. / Wishart, G. / Yates, D. / Dominguez, C. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5a2s.cif.gz | 153.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5a2s.ent.gz | 119.8 KB | Display | PDB format |
PDBx/mmJSON format | 5a2s.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/a2/5a2s ftp://data.pdbj.org/pub/pdb/validation_reports/a2/5a2s | HTTPS FTP |
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-Related structure data
Related structure data | 4cbyS S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 42755.559 Da / Num. of mol.: 2 / Fragment: HISTONE DEACETYLASE 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 | #3: Chemical | ChemComp-ZN / #4: Chemical | #5: Water | ChemComp-HOH / | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.1 Å3/Da / Density % sol: 40 % / Description: NONE |
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Crystal grow | Details: 24% W/V PEG 3350, 0.2 M AMMONIUM ACETATE, 0.1 M BIS-TRIS PH 5.5, 10 MM PROLINE |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 |
Detector | Type: ADSC CCD / Detector: CCD / Date: Aug 15, 2012 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9795 Å / Relative weight: 1 |
Reflection | Resolution: 2.65→30 Å / Num. obs: 20994 / % possible obs: 99.2 % / Observed criterion σ(I): 2 / Redundancy: 7.1 % / Rmerge(I) obs: 0.18 / Net I/σ(I): 11.2 |
Reflection shell | Resolution: 2.65→2.72 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.72 / Mean I/σ(I) obs: 2.4 / % possible all: 90.1 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 4CBY Resolution: 2.65→161.63 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.873 / SU B: 12.401 / SU ML: 0.257 / Cross valid method: THROUGHOUT / ESU R Free: 0.375 / Stereochemistry target values: MAXIMUM LIKELIHOOD Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.U VALUES REFINED INDIVIDUALLY.
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 21.947 Å2
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Refinement step | Cycle: LAST / Resolution: 2.65→161.63 Å
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