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Title: Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

Abstract

Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®), romidepsin (FK228, Istodax®), belinostat (Beleodaq®), and panobinostat (Farydak®). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. In this paper we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98 Å resolution. We also describe the use of molecular docking studies to explore the binding interactionsmore » of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition.« less

Authors:
 [1];  [2];  [1];  [3];  [1]
  1. Christopher Newport Univ., Newport News, VA (United States)
  2. Ithaca College, NY (United States)
  3. Argonne National Lab. (ANL), Argonne, IL (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Office of Research Infrastructure Programs (ORIP); USDOE Office of Science (SC)
OSTI Identifier:
1324808
Alternate Identifier(s):
OSTI ID: 1359493
Grant/Contract Number:  
P41 GM103403; S10 RR029205; AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Structural Biology
Additional Journal Information:
Journal Volume: 195; Journal Issue: 3; Journal ID: ISSN 1047-8477
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Histone deacetylase 8; Histone deacetylase inhibitors (HDACi); Hydroxamic acids; AutoDock Vina

Citation Formats

Tabackman, Alexa A., Frankson, Rochelle, Marsan, Eric S., Perry, Kay, and Cole, Kathryn E. Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket. United States: N. p., 2016. Web. doi:10.1016/j.jsb.2016.06.023.
Tabackman, Alexa A., Frankson, Rochelle, Marsan, Eric S., Perry, Kay, & Cole, Kathryn E. Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket. United States. https://doi.org/10.1016/j.jsb.2016.06.023
Tabackman, Alexa A., Frankson, Rochelle, Marsan, Eric S., Perry, Kay, and Cole, Kathryn E. Wed . "Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket". United States. https://doi.org/10.1016/j.jsb.2016.06.023. https://www.osti.gov/servlets/purl/1324808.
@article{osti_1324808,
title = {Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket},
author = {Tabackman, Alexa A. and Frankson, Rochelle and Marsan, Eric S. and Perry, Kay and Cole, Kathryn E.},
abstractNote = {Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®), romidepsin (FK228, Istodax®), belinostat (Beleodaq®), and panobinostat (Farydak®). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. In this paper we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98 Å resolution. We also describe the use of molecular docking studies to explore the binding interactions of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition.},
doi = {10.1016/j.jsb.2016.06.023},
journal = {Journal of Structural Biology},
number = 3,
volume = 195,
place = {United States},
year = {Wed Jun 29 00:00:00 EDT 2016},
month = {Wed Jun 29 00:00:00 EDT 2016}
}

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