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A cellular chemical probe targeting the chromodomains of Polycomb Repressive Complex 1

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 chromo...

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Autores principales: Stuckey, Jacob I, Dickson, Bradley M, Cheng, Nancy, Liu, Yanli, Norris, Jacqueline L, Cholensky, Stephanie H, Tempel, Wolfram, Qin, Su, Huber, Katherine G, Sagum, Cari, 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, Cheryl H, James, Lindsey I, Frye, Stephen V
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755828/
https://www.ncbi.nlm.nih.gov/pubmed/26807715
http://dx.doi.org/10.1038/nchembio.2007
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author Stuckey, Jacob I
Dickson, Bradley M
Cheng, Nancy
Liu, Yanli
Norris, Jacqueline L
Cholensky, Stephanie H
Tempel, Wolfram
Qin, Su
Huber, Katherine G
Sagum, Cari
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, Cheryl H
James, Lindsey I
Frye, Stephen V
author_facet Stuckey, Jacob I
Dickson, Bradley M
Cheng, Nancy
Liu, Yanli
Norris, Jacqueline L
Cholensky, Stephanie H
Tempel, Wolfram
Qin, Su
Huber, Katherine G
Sagum, Cari
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, Cheryl H
James, Lindsey I
Frye, Stephen V
author_sort Stuckey, Jacob I
collection PubMed
description 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 K(d) of ∼100 nM for each, and is 6- to 18-fold selective versus seven other CBX and CDY chromodomains while being highly selective versus >250 other protein targets. X-ray crystallography revealed that UNC3866 closely mimics the interactions of the methylated H3 tail with these chromodomains. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform-dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, a known CBX7 phenotype, while UNC4219, a methylated negative control compound, has negligible effects.
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spelling pubmed-47558282016-07-25 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, Wolfram Qin, Su Huber, Katherine G Sagum, Cari 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, Cheryl H James, Lindsey I Frye, Stephen V Nat Chem Biol Article 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 K(d) of ∼100 nM for each, and is 6- to 18-fold selective versus seven other CBX and CDY chromodomains while being highly selective versus >250 other protein targets. X-ray crystallography revealed that UNC3866 closely mimics the interactions of the methylated H3 tail with these chromodomains. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform-dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, a known CBX7 phenotype, while UNC4219, a methylated negative control compound, has negligible effects. 2016-01-25 2016-03 /pmc/articles/PMC4755828/ /pubmed/26807715 http://dx.doi.org/10.1038/nchembio.2007 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Stuckey, Jacob I
Dickson, Bradley M
Cheng, Nancy
Liu, Yanli
Norris, Jacqueline L
Cholensky, Stephanie H
Tempel, Wolfram
Qin, Su
Huber, Katherine G
Sagum, Cari
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, Cheryl H
James, Lindsey I
Frye, Stephen V
A cellular chemical probe targeting the chromodomains of Polycomb Repressive Complex 1
title A cellular chemical probe targeting the chromodomains of Polycomb Repressive Complex 1
title_full A cellular chemical probe targeting the chromodomains of Polycomb Repressive Complex 1
title_fullStr A cellular chemical probe targeting the chromodomains of Polycomb Repressive Complex 1
title_full_unstemmed A cellular chemical probe targeting the chromodomains of Polycomb Repressive Complex 1
title_short A cellular chemical probe targeting the chromodomains of Polycomb Repressive Complex 1
title_sort cellular chemical probe targeting the chromodomains of polycomb repressive complex 1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755828/
https://www.ncbi.nlm.nih.gov/pubmed/26807715
http://dx.doi.org/10.1038/nchembio.2007
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