Selective Inhibition of CBX6: A Methyllysine Reader Protein in the Polycomb Family.

Autor:	Milosevich N; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Gignac MC; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., McFarlane J; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Simhadri C; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Horvath S; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Daze KD; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Croft CS; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Dheri A; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Quon TT; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Douglas SF; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Wulff JE; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Paci I; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada., Hof F; Department of Chemistry, University of Victoria , Victoria, V8W 3V6, Canada.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2015 Dec 07; Vol. 7 (2), pp. 139-44. Date of Electronic Publication: 2015 Dec 07 (Print Publication: 2016).
DOI:	10.1021/acsmedchemlett.5b00378
Abstrakt:	The polycomb paralogs CBX2, CBX4, CBX6, CBX7, and CBX8 are epigenetic readers that rely on "aromatic cage" motifs to engage their partners' methyllysine side chains. Each CBX carries out distinct functions, yet each includes a highly similar methyllysine-reading chromodomain as a key element. CBX7 is the only chromodomain that has yet been targeted by chemical inhibition. We report a small set of peptidomimetic agents in which a simple chemical modification switches the ligands from one with promiscuity across all polycomb paralogs to one that provides selective inhibition of CBX6. The structural basis for this selectivity, which involves occupancy of a small hydrophobic pocket adjacent to the aromatic cage, was confirmed through molecular dynamics simulations. Our results demonstrate the increases in affinity and selectivity generated by ligands that engage extended regions of chromodomain binding surfaces.
Databáze:	MEDLINE
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