A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1

Stuckey, Jacob I.; Dickson, Bradley M.; Cheng, Nancy; Liu, Yanli; Norris, Jacqueline L.; Cholensky, Stephanie H.; Tempel, W.; Su, Qin; Huber, Katherine G; Sagum, Cari A.; Black, Karynne; Li, Fengling; Huang, Xi Ping; Roth, Bryan L.; Baughman, Brandi M.; Senisterra, Guillermo; Pattenden, Samantha G.; Vedadi, Masoud; Brown, Peter J.; Bedford, Mark T.; Min, Jinrong; Arrowsmith, C.H.; James, Lindsey I.; Frye, Stephen V.

doi:10.1038/nchembio.2007

Cited by 142 publications

(243 citation statements)

References 60 publications

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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%

“…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%

See 1 more Smart Citation

Genomic targeting of epigenetic probes using a chemically tailored Cas9 system

Liszczak

Brown

Kim

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Recent advances in the field of programmable DNA-binding proteins have led to the development of facile methods for genomic localization of genetically encodable entities. Despite the extensive utility of these tools, locus-specific delivery of synthetic molecules remains limited by a lack of adequate technologies. Here we combine the flexibility of chemical synthesis with the specificity of a programmable DNA-binding protein by using protein trans-splicing to ligate synthetic elements to a nuclease-deficient Cas9 (dCas9) in vitro and subsequently deliver the dCas9 cargo to live cells. The versatility of this technology is demonstrated by delivering dCas9 fusions that include either the small-molecule bromodomain and extra-terminal family bromodomain inhibitor JQ1 or a peptide-based PRC1 chromodomain ligand, which are capable of recruiting endogenous copies of their cognate binding partners to targeted genomic binding sites. We expect that this technology will allow for the genomic localization of a wide array of small molecules and modified proteinaceous materials.

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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%

Section: Resultsmentioning

confidence: 99%

Genomic targeting of epigenetic probes using a chemically tailored Cas9 system

Liszczak

Brown

Kim

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…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%

Developing Spindlin1 small-molecule inhibitors by using protein microarrays

Bae

Viviano

et al. 2017

Nat Chem Biol

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The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the “druggability” of epigenetic effector molecules. The small molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains, and with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs we screened a protein domain microarray of human methyl-lysine effector molecules to rapidly detect compounds with novel binding profiles - either improved or loosened specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of more selective SPIN1 inhibitors (EML631–633), which engage SPIN1 in cells, block its ability to “read” H3K4me3 marks, and inhibit its transcriptional coactivator activity. Protein microarrays can thus be used as a platform to “target hop” and identify small molecules that bind and compete with domain–motif interactions.

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“…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%

Overcoming time scale and finite size limitations to compute nucleation rates from small scale well tempered metadynamics simulations

Salvalaglio

Tiwary

Maggioni

et al. 2016

The Journal of Chemical Physics

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Condensation of a liquid droplet from a supersaturated vapour phase is initiated by a prototypical nucleation event. As such it is challenging to compute its rate from atomistic molecular dynamics simulations. In fact at realistic supersaturation conditions condensation occurs on time scales that far exceed what can be reached with conventional molecular dynamics methods. Another known problem in this context is the distortion of the free energy profile associated to nucleation due to the small, finite size of typical simulation boxes. In this work the problem of time scale is addressed with a recently developed enhanced sampling method while contextually correcting for finite size effects. We demonstrate our approach by studying the condensation of argon, and showing that characteristic nucleation times of the order of magnitude of hours can be reliably calculated, approaching realistic supersaturation conditions, thus bridging the gap between what standard molecular dynamics simulations can do and real physical systems.

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A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1

Cited by 142 publications

References 60 publications

Genomic targeting of epigenetic probes using a chemically tailored Cas9 system

Genomic targeting of epigenetic probes using a chemically tailored Cas9 system

Developing Spindlin1 small-molecule inhibitors by using protein microarrays

Overcoming time scale and finite size limitations to compute nucleation rates from small scale well tempered metadynamics simulations

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