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://dx.doi.org/10.1021/acs.jmedchem.8b01087. |
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@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 = {http://dx.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://dx.doi.org/10.1021/acs.jmedchem.8b01087.
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