Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

Martin Marek 1 Tajith Shaik 1 Tino Heimburg 2 Alokta Chakrabarti 3 Julien Lancelot 4 Elizabeth Ramos-Morales 1 Cyrielle da Veiga 5 Dmitrii Kalinin 6 Jelena Melesina 2 Dina Robaa 2 Karin Schmidtkunz 3 Takayoshi Suzuki 7, 8 Ralph Holl 9 Eric Ennifar 5 Raymond Pierce 4 Manfred Jung 3 Wolfang Sippl 2 Christophe Romier 1
1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 MLU - Martin-Luther-Universität Halle Wittenberg
3 Albert-Ludwigs-Universität Freiburg
4 CIIL - Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204
5 IBMC - Institut de biologie moléculaire et cellulaire
6 University of Münster
7 Kyoto Prefectural University of Medicine [Kyoto, Japon]
8 CREST - Core Research for Evolutional Science and Technology
9 University of Hamburg
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.
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https://hal-cnrs.archives-ouvertes.fr/hal-02118693
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Submitted on : Friday, May 3, 2019 - 11:40:11 AM
Last modification on : Friday, July 19, 2019 - 1:14:04 AM

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Martin Marek, Tajith Shaik, Tino Heimburg, Alokta Chakrabarti, Julien Lancelot, et al.. Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants. Journal of Medicinal Chemistry, American Chemical Society, 2018, 61 (22), pp.10000-10016. ⟨10.1021/acs.jmedchem.8b01087⟩. ⟨hal-02118693⟩

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