2016
DOI: 10.1038/nchembio.2007
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A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1

Abstract: We report the design and characterization of UNC3866, a potent antagonist of the methyl-lysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb Repressive Complex 1 to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently with a Kd of ∼100 nM for each, and is 6- to 18-fold selective versus seven other CBX and CDY chromodomains while being highly selective versus … Show more

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Cited by 136 publications
(229 citation statements)
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“…5E). This result confirms the localization of multiple PRC1 complex components, because UNC3866 can only recruit Ring1b via its interaction with the Cbx subunits (35).…”
Section: Resultssupporting
confidence: 71%
See 1 more Smart Citation
“…5E). This result confirms the localization of multiple PRC1 complex components, because UNC3866 can only recruit Ring1b via its interaction with the Cbx subunits (35).…”
Section: Resultssupporting
confidence: 71%
“…This complex is composed of a minimum of four protein subunits with varying numbers of homologs, including the chromobox protein family (Cbx) that interacts with modified histone H3 (H3K27me3) to recruit the complex to chromatin (33,34). Importantly, a recently developed high-affinity peptide ligand for Cbx proteins, UNC3866 (35), has a structure and properties that seem well suited for locus-specific PRC1 recruitment via our dCas9 conjugation approach (Fig. 5 A and B).…”
Section: Resultsmentioning
confidence: 99%
“…We then expanded this approach to investigate methyl-reading domains, which could interpret the histone code 34 . More recently, we have used this domain array approach to establish the selectivity of small molecules that bind protein domains 21,25 . In these latter screens, we developed lead compounds that inhibited MBT domains (UNC1215) and chromodomain (UNC3866) methyl-dependent interactions.…”
Section: Discussionmentioning
confidence: 99%
“…Moreover, many of these domain types are predicted to be very druggable 17 . Thus, there has been a focused attempt by a number of groups to identify compounds that can inhibit methyl-dependent protein-protein interactions, including small molecules that competitively inhibit PHD finger binding 18,19 , the development of potent H3K27me3 peptide mimetics which selectively inhibit protein interactions that are Chromo domain mediated 20,21 , and the employment of virtual screening strategy to identify small-molecule ligands for MBT domains 22 and Tudor domains 23 . The MBT domain ligands are a series of nicotinamides, which do not bind PHD or Chromo domains 24 .…”
Section: Introductionmentioning
confidence: 99%
“…When this is the case, the whole transition time distribution can be recovered from a set of WTmetaD simulations. This approach has been applied to several problems, thus allowing the computation of rates of activated processes such as DNA unfolding 16 , and protein-ligand unbinding [17][18][19] .…”
Section: A From Metadynamics To Dynamicsmentioning
confidence: 99%