5W5K
Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with KV70
Summary for 5W5K
| Entry DOI | 10.2210/pdb5w5k/pdb |
| Descriptor | Histone deacetylase 6, ZINC ION, POTASSIUM ION, ... (5 entities in total) |
| Functional Keywords | histone deacetylase, hydrolase, tubulin deacetylase |
| Biological source | Danio rerio (Zebrafish) |
| Total number of polymer chains | 3 |
| Total formula weight | 122338.51 |
| Authors | Porter, N.J.,Christianson, D.W. (deposition date: 2017-06-15, release date: 2018-06-27, Last modification date: 2023-10-04) |
| Primary citation | Vogerl, K.,Ong, N.,Senger, J.,Herp, D.,Schmidtkunz, K.,Marek, M.,Muller, M.,Bartel, K.,Shaik, T.B.,Porter, N.J.,Robaa, D.,Christianson, D.W.,Romier, C.,Sippl, W.,Jung, M.,Bracher, F. Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors. J.Med.Chem., 62:1138-1166, 2019 Cited by PubMed Abstract: The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation and systematic variation of phenothiazines and their analogues containing a benzhydroxamic acid moiety as the zinc-binding group. We evaluated their ability to selectively inhibit HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6. PubMed: 30645113DOI: 10.1021/acs.jmedchem.8b01090 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
Download full validation report
