Characterization of Histone Deacetylase 8 ...
Document type :
Compte-rendu et recension critique d'ouvrage
PMID :
Title :
Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants
Author(s) :
Marek, Martin [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Shaik, Tajith [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Heimburg, Tino [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Chakrabarti, Alokta [Auteur]
Albert-Ludwigs-Universität Freiburg
Lancelot, Julien [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Ramos-Morales, Elizabeth [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
da Veiga, Cyrielle [Auteur]
Institut de biologie moléculaire et cellulaire [IBMC]
Kalinin, Dmitrii [Auteur]
Westfälische Wilhelms-Universität Münster = University of Münster [WWU]
Melesina, Jelena [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Robaa, Dina [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Schmidtkunz, Karin [Auteur]
Albert-Ludwigs-Universität Freiburg
Suzuki, Takayoshi [Auteur]
Core Research for Evolutional Science and Technology [CREST]
Kyoto Prefectural University of Medicine [Kyoto, Japon]
Holl, Ralph [Auteur]
University of Hamburg
Ennifar, Eric [Auteur]
Institut de biologie moléculaire et cellulaire [IBMC]
Pierce, Raymond [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Jung, Manfred [Auteur]
Albert-Ludwigs-Universität Freiburg
Sippl, Wolfang [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Romier, Christophe [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Shaik, Tajith [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Heimburg, Tino [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Chakrabarti, Alokta [Auteur]
Albert-Ludwigs-Universität Freiburg
Lancelot, Julien [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Ramos-Morales, Elizabeth [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
da Veiga, Cyrielle [Auteur]
Institut de biologie moléculaire et cellulaire [IBMC]
Kalinin, Dmitrii [Auteur]
Westfälische Wilhelms-Universität Münster = University of Münster [WWU]
Melesina, Jelena [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Robaa, Dina [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Schmidtkunz, Karin [Auteur]
Albert-Ludwigs-Universität Freiburg
Suzuki, Takayoshi [Auteur]
Core Research for Evolutional Science and Technology [CREST]
Kyoto Prefectural University of Medicine [Kyoto, Japon]
Holl, Ralph [Auteur]
University of Hamburg
Ennifar, Eric [Auteur]
Institut de biologie moléculaire et cellulaire [IBMC]
Pierce, Raymond [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Jung, Manfred [Auteur]
Albert-Ludwigs-Universität Freiburg
Sippl, Wolfang [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Romier, Christophe [Auteur]
Institut de Génétique et de Biologie Moléculaire et Cellulaire [IGBMC]
Journal title :
Journal of Medicinal Chemistry
Pages :
10000-10016
Publisher :
American Chemical Society
Publication date :
2018-10-29
ISSN :
0022-2623
HAL domain(s) :
Sciences du Vivant [q-bio]
Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire
Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire
English abstract : [en]
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 ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Popular science :
Non
ANR Project :
Source :
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