5wgm

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with ACY-1083

spinqualitylabelsall models 5wgm, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5wgm is a 3 chain structure with sequence from Danio rerio. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: AH7, EDO, K, PEG, PGE, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function F8W4B7_DANRE Publication Abstract from PubMed Histone deacetylases (HDACs) regulate myriad cellular processes by catalyzing the hydrolysis of acetyl-l-lysine residues in histone and nonhistone proteins. The Zn(2+)-dependent class IIb enzyme HDAC6 regulates microtubule function by deacetylating alpha-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 Zn(2+) 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(2+)-binding conformers for the inhibitor: a major conformer (70%) with canonical bidentate hydroxamate-Zn(2+) coordination geometry and a minor conformer (30%) with monodentate hydroxamate-Zn(2+) 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. Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors.,Porter NJ, Mahendran A, Breslow R, Christianson DW Proc Natl Acad Sci U S A. 2017 Dec 4. pii: 1718823114. doi:, 10.1073/pnas.1718823114. PMID:29203661 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone deacetylase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA