AI Article Synopsis
- The polycomb paralogs CBX2, CBX4, CBX6, CBX7, and CBX8 are crucial epigenetic readers that interact with methyllysine side chains using similar chromodomains, but each has unique functions.
- CBX7 is notable for being the only chromodomain without a chemical inhibition method available, prompting a study on peptidomimetics that can selectively inhibit other paralogs.
- The research revealed a set of agents that, through slight chemical modification, can switch from affecting multiple polycomb proteins to specifically inhibiting CBX6, confirmed by molecular dynamics simulations showing enhanced binding affinity due to engagement of the chromodomain's extended binding surface.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753544 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.5b00378 | DOI Listing |
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