6ZW1
X-ray structure of Danio rerio histone deacetylase 6 (HDAC6) CD2 in complex with an inhibitor SW101
Summary for 6ZW1
| Entry DOI | 10.2210/pdb6zw1/pdb |
| Descriptor | Histone deacetylase 6, ZINC ION, 1-[[4-(oxidanylcarbamoyl)phenyl]methyl]-3,4-dihydro-2~{H}-quinoline-6-carboxamide, ... (7 entities in total) |
| Functional Keywords | histone deacetylase, deacetylation, inhibitor, danio rerio, hydrolase |
| Biological source | Danio rerio (Zebrafish) |
| Total number of polymer chains | 1 |
| Total formula weight | 40668.44 |
| Authors | Barinka, C.,Motlova, L.,Ustinova, K. (deposition date: 2020-07-27, release date: 2021-08-04, Last modification date: 2024-01-31) |
| Primary citation | Shen, S.,Picci, C.,Ustinova, K.,Benoy, V.,Kutil, Z.,Zhang, G.,Tavares, M.T.,Pavlicek, J.,Zimprich, C.A.,Robers, M.B.,Van Den Bosch, L.,Barinka, C.,Langley, B.,Kozikowski, A.P. Tetrahydroquinoline-Capped Histone Deacetylase 6 Inhibitor SW-101 Ameliorates Pathological Phenotypes in a Charcot-Marie-Tooth Type 2A Mouse Model. J.Med.Chem., 64:4810-4840, 2021 Cited by PubMed Abstract: Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (). Importantly, we demonstrate that SW-101 () treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant 2. Taken together, these results bode well for the further development of SW-101 () as a disease-modifying HDAC6i. PubMed: 33830764DOI: 10.1021/acs.jmedchem.0c02210 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.13 Å) |
Structure validation
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