6HSK
Crystal structure of a human HDAC8 L6 loop mutant complexed with Quisinostat
Summary for 6HSK
| Entry DOI | 10.2210/pdb6hsk/pdb |
| Descriptor | Histone deacetylase 8, ZINC ION, POTASSIUM ION, ... (5 entities in total) |
| Functional Keywords | epigenetics, histone deacetylase, hdac8, selective inhibitor, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 85301.68 |
| Authors | Marek, M.,Shaik, T.B.,Ramos-Morales, E.,Romier, C. (deposition date: 2018-10-01, release date: 2018-10-31, Last modification date: 2024-01-24) |
| Primary citation | Marek, M.,Shaik, T.B.,Heimburg, T.,Chakrabarti, A.,Lancelot, J.,Ramos-Morales, E.,Da Veiga, C.,Kalinin, D.,Melesina, J.,Robaa, D.,Schmidtkunz, K.,Suzuki, T.,Holl, R.,Ennifar, E.,Pierce, R.J.,Jung, M.,Sippl, W.,Romier, C. Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants. J. Med. Chem., 61:10000-10016, 2018 Cited by PubMed Abstract: Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs. PubMed: 30347148DOI: 10.1021/acs.jmedchem.8b01087 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.096 Å) |
Structure validation
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