Selective Inhibition of CBX6: A Methyllysine Reader Protein in the Polycomb Family
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- 作者：Natalia Milosevich ; Michael C. Gignac ; James McFarlane ; Chakravarthi Simhadri ; Shanti Horvath ; Kevin D. Daze ; Caitlin S. Croft ; Aman Dheri ; Taylor T. H. Quon ; Sarah F. Douglas ; Jeremy E. Wulff ; Irina Paci ; Fraser Hof
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：February 11, 2016
- 年：2016
- 卷：7
- 期：2
- 页码：139-144
- 全文大小：347K
- ISSN：1948-5875
文摘
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.