PUBLICATION
Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6
- Authors
- Osko, J.D., Porter, N.J., Narayana Reddy, P.A., Xiao, Y.C., Rokka, J., Jung, M., Hooker, J.M., Salvino, J.M., Christianson, D.W.
- ID
- ZDB-PUB-200701-24
- Date
- 2020
- Source
- Journal of medicinal chemistry 63: 295-308 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Catalytic Domain
- Histone Deacetylase 6/antagonists & inhibitors*
- Histone Deacetylase 6/metabolism*
- Histone Deacetylase Inhibitors/chemical synthesis
- Histone Deacetylase Inhibitors/chemistry
- Histone Deacetylase Inhibitors/metabolism*
- Hydrophobic and Hydrophilic Interactions
- Hydroxamic Acids/chemical synthesis
- Hydroxamic Acids/chemistry
- Hydroxamic Acids/metabolism*
- Molecular Structure
- Protein Binding
- Structure-Activity Relationship
- Zebrafish
- Zebrafish Proteins/antagonists & inhibitors*
- Zebrafish Proteins/metabolism*
- PubMed
- 31793776 Full text @ J. Med. Chem.
Citation
Osko, J.D., Porter, N.J., Narayana Reddy, P.A., Xiao, Y.C., Rokka, J., Jung, M., Hooker, J.M., Salvino, J.M., Christianson, D.W. (2020) Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6. Journal of medicinal chemistry. 63:295-308.
Abstract
Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping