PUBLICATION
Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors
- Authors
- Porter, N.J., Mahendran, A., Breslow, R., Christianson, D.W.
- ID
- ZDB-PUB-171206-6
- Date
- 2017
- Source
- Proceedings of the National Academy of Sciences of the United States of America 114(51): 13459-13464 (Journal)
- Registered Authors
- Keywords
- cancer chemotherapy, drug discovery, enzyme inhibitor, metalloenzyme, protein crystallography
- MeSH Terms
-
- Animals
- Binding Sites
- Histone Deacetylase 6/antagonists & inhibitors
- Histone Deacetylase 6/chemistry*
- Histone Deacetylase 6/metabolism
- Histone Deacetylase Inhibitors/chemistry
- Histone Deacetylase Inhibitors/pharmacology*
- Hydroxamic Acids/chemistry
- Hydroxamic Acids/pharmacology*
- Molecular Docking Simulation*
- Protein Binding
- Zebrafish
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/metabolism
- Zinc/chemistry
- Zinc/metabolism
- PubMed
- 29203661 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Porter, N.J., Mahendran, A., Breslow, R., Christianson, D.W. (2017) Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors. Proceedings of the National Academy of Sciences of the United States of America. 114(51):13459-13464.
Abstract
Histone deacetylases (HDACs) regulate myriad cellular processes by catalyzing the hydrolysis of acetyl-l-lysine residues in histone and nonhistone proteins. The Zn2+-dependent class IIb enzyme HDAC6 regulates microtubule function by deacetylating α-tubulin, which suppresses microtubule dynamics and leads to cell cycle arrest and apoptosis. Accordingly, HDAC6 is a target for the development of selective inhibitors that might be useful in new therapeutic approaches for the treatment of cancer, neurodegenerative diseases, and other disorders. Here, we present high-resolution structures of catalytic domain 2 from Danio rerio HDAC6 (henceforth simply "HDAC6") complexed with compounds that selectively inhibit HDAC6 while maintaining nanomolar inhibitory potency: N-hydroxy-4-[(N(2-hydroxyethyl)-2-phenylacetamido)methyl)-benzamide)] (HPB), ACY-1215 (Ricolinostat), and ACY-1083. These structures reveal that an unusual monodentate Zn2+ coordination mode is exploited by sterically bulky HDAC6-selective phenylhydroxamate inhibitors. We additionally report the ultrahigh-resolution structure of the HDAC6-trichostatin A complex, which reveals two Zn2+-binding conformers for the inhibitor: a major conformer (70%) with canonical bidentate hydroxamate-Zn2+ coordination geometry and a minor conformer (30%) with monodentate hydroxamate-Zn2+ coordination geometry, reflecting a free energy difference of only 0.5 kcal/mol. The minor conformer is not visible in lower resolution structure determinations. Structural comparisons of HDAC6-inhibitor complexes with class I HDACs suggest active site features that contribute to the isozyme selectivity observed in biochemical assays.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping