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

J 2018

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

MAREK, Martin; Tajith B. SHAIK; Tino HEIMBURG; Alokta CHAKRABARTI; Julien LANCELOT et al.

Základní údaje

Originální název

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

Autoři

Vydání

Journal of Medicinal Chemistry, Washington, American Chemical Society, 2018, 0022-2623

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30107 Medicinal chemistry

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.054

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/18:00106140

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

EFFICIENT GENERATION; SCHISTOSOMA-MANSONI; CANCER EPIGENETICS; CRYSTAL-STRUCTURE; MOLECULAR-BASIS; AM1-BCC MODEL; ACETYLATION; MECHANISM; TRANSCRIPTION; CORNELIA

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 9. 2. 2019 20:50, Mgr. Michaela Hylsová, Ph.D.

Anotace

V originále

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.

Citovat

MAREK, Martin; Tajith B. SHAIK; Tino HEIMBURG; Alokta CHAKRABARTI; Julien LANCELOT; Elizabeth RAMOS-MORALES; Cyrielle DA VEIGA; Dmitrii KALININ; Jelena MELESINA; Dina ROBAA; Karin SCHMIDTKUNZ; Takayoshi SUZUKI; Ralph HOLL; Eric ENNIFAR; Raymond J. PIERCE; Manfred JUNG; Wolfgang SIPPL a Christophe ROMIER. Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants. Journal of Medicinal Chemistry. Washington: American Chemical Society, 2018, roč. 61, č. 22, s. 10000-10016. ISSN 0022-2623. Dostupné z: https://doi.org/10.1021/acs.jmedchem.8b01087.

@article{1495536,
   author = {Marek, Martin and Shaik, Tajith B. and Heimburg, Tino and Chakrabarti, Alokta and Lancelot, Julien and RamosandMorales, Elizabeth and Da Veiga, Cyrielle and Kalinin, Dmitrii and Melesina, Jelena and Robaa, Dina and Schmidtkunz, Karin and Suzuki, Takayoshi and Holl, Ralph and Ennifar, Eric and Pierce, Raymond J. and Jung, Manfred and Sippl, Wolfgang and Romier, Christophe},
   article_location = {Washington},
   article_number = {22},
   doi = {https://doi.org/10.1021/acs.jmedchem.8b01087},
   keywords = {EFFICIENT GENERATION; SCHISTOSOMA-MANSONI; CANCER EPIGENETICS; CRYSTAL-STRUCTURE; MOLECULAR-BASIS; AM1-BCC MODEL; ACETYLATION; MECHANISM; TRANSCRIPTION; CORNELIA},
   language = {eng},
   issn = {0022-2623},
   journal = {Journal of Medicinal Chemistry},
   title = {Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants},
   url = {https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01087},
   volume = {61},
   year = {2018}
}

TY  - JOUR
ID  - 1495536
AU  - Marek, Martin - Shaik, Tajith B. - Heimburg, Tino - Chakrabarti, Alokta - Lancelot, Julien - Ramos-Morales, Elizabeth - Da Veiga, Cyrielle - Kalinin, Dmitrii - Melesina, Jelena - Robaa, Dina - Schmidtkunz, Karin - Suzuki, Takayoshi - Holl, Ralph - Ennifar, Eric - Pierce, Raymond J. - Jung, Manfred - Sippl, Wolfgang - Romier, Christophe
PY  - 2018
TI  - Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants
JF  - Journal of Medicinal Chemistry
VL  - 61
IS  - 22
SP  - 10000-10016
EP  - 10000-10016
PB  - American Chemical Society
SN  - 00222623
KW  - EFFICIENT GENERATION
KW  - SCHISTOSOMA-MANSONI
KW  - CANCER EPIGENETICS
KW  - CRYSTAL-STRUCTURE
KW  - MOLECULAR-BASIS
KW  - AM1-BCC MODEL
KW  - ACETYLATION
KW  - MECHANISM
KW  - TRANSCRIPTION
KW  - CORNELIA
UR  - https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01087
L2  - https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01087
N2  - 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.
ER  -

MAREK, Martin; Tajith B. SHAIK; Tino HEIMBURG; Alokta CHAKRABARTI; Julien LANCELOT; Elizabeth RAMOS-MORALES; Cyrielle DA VEIGA; Dmitrii KALININ; Jelena MELESINA; Dina ROBAA; Karin SCHMIDTKUNZ; Takayoshi SUZUKI; Ralph HOLL; Eric ENNIFAR; Raymond J. PIERCE; Manfred JUNG; Wolfgang SIPPL a Christophe ROMIER. Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants. \textit{Journal of Medicinal Chemistry}. Washington: American Chemical Society, 2018, roč.~61, č.~22, s.~10000-10016. ISSN~0022-2623. Dostupné z: https://doi.org/10.1021/acs.jmedchem.8b01087.

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