5WGI

Ultrahigh resolution crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with TSA

Summary for 5WGI

• Entry DOI: 10.2210/pdb5wgi/pdb
• Descriptor: Hdac6 protein, ZINC ION, TRICHOSTATIN A, ... (10 entities in total)
• Functional Keywords: histone deacetylase, hydrolase inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Danio rerio (Zebrafish)
• Total number of polymer chains: 1
• Total formula weight: 41909.25

Authors

Porter, N.J.,Christianson, D.W. (deposition date: 2017-07-14, release date: 2017-12-06, Last modification date: 2023-10-04)

Primary citation

Porter, N.J.,Mahendran, A.,Breslow, R.,Christianson, D.W.
Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors.
Proc. Natl. Acad. Sci. U.S.A., 114:13459-13464, 2017

PubMed Abstract: Histone deacetylases (HDACs) regulate myriad cellular processes by catalyzing the hydrolysis of acetyl-l-lysine residues in histone and nonhistone proteins. The Zn-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 HDAC6 (henceforth simply "HDAC6") complexed with compounds that selectively inhibit HDAC6 while maintaining nanomolar inhibitory potency: -hydroxy-4-[((2-hydroxyethyl)-2-phenylacetamido)methyl)-benzamide)] (HPB), ACY-1215 (Ricolinostat), and ACY-1083. These structures reveal that an unusual monodentate Zn 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 Zn-binding conformers for the inhibitor: a major conformer (70%) with canonical bidentate hydroxamate-Zn coordination geometry and a minor conformer (30%) with monodentate hydroxamate-Zn 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.

PubMed: 29203661
DOI: 10.1073/pnas.1718823114

Experimental method

X-RAY DIFFRACTION (1.05 Å)