Download MendeleyCharacterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
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.(2018) J Med Chem 61: 10000-10016
- PubMed: 30347148
- DOI: https://doi.org/10.1021/acs.jmedchem.8b01087
- Primary Citation of Related Structures:
6HQY, 6HRQ, 6HSF, 6HSG, 6HSH, 6HSK, 6HSZ, 6HT8, 6HTG, 6HTH, 6HTI, 6HTT, 6HTZ, 6HU0, 6HU1, 6HU2, 6HU3 - 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.
Organizational Affiliation:
Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Département de Biologie Structurale Intégrative , Université de Strasbourg, Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM U1258) , 1 rue Laurent Fries , 67404 Illkirch Cedex , France.
