Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6.
Jeremy D OskoNicholas J PorterPoli Adi Narayana ReddyYou-Cai XiaoJohanna RokkaManfred JungJacob M HookerJoseph M SalvinoDavid W ChristiansonPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- histone deacetylase
- crystal structure
- high resolution
- chemotherapy induced
- amino acid
- transcription factor
- squamous cell carcinoma
- computed tomography
- magnetic resonance imaging
- magnetic resonance
- cancer therapy
- drug delivery
- dual energy
- mass spectrometry
- combination therapy
- capillary electrophoresis
- single molecule
- solid phase extraction
- structural basis