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Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain
We describe the discovery of UNC1215, a potent and selective chemical probe for the methyl-lysine (Kme) reading function of L3MBTL3, a member of the malignant brain tumor (MBT) family of chromatin interacting transcriptional repressors. UNC1215 binds L3MBTL3 with a K(d) of 120 nM, competitively disp...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577944/ https://www.ncbi.nlm.nih.gov/pubmed/23292653 http://dx.doi.org/10.1038/nchembio.1157 |
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author | James, Lindsey I. Barsyte-Lovejoy, Dalia Zhong, Nan Krichevsky, Liubov Korboukh, Victoria K. Herold, Martin J. MacNevin, Christopher J. Norris, Jacqueline L. Sagum, Cari A. Tempel, Wolfram Marcon, Edyta Guo, Hongbo Gao, Cen Huang, Xi-Ping Duan, Shili Emili, Andrew Greenblatt, Jack F. Kireev, Dmitri B. Jin, Jian Janzen, William P. Brown, Peter J. Bedford, Mark T. Arrowsmith, Cheryl H. Frye, Stephen V. |
author_facet | James, Lindsey I. Barsyte-Lovejoy, Dalia Zhong, Nan Krichevsky, Liubov Korboukh, Victoria K. Herold, Martin J. MacNevin, Christopher J. Norris, Jacqueline L. Sagum, Cari A. Tempel, Wolfram Marcon, Edyta Guo, Hongbo Gao, Cen Huang, Xi-Ping Duan, Shili Emili, Andrew Greenblatt, Jack F. Kireev, Dmitri B. Jin, Jian Janzen, William P. Brown, Peter J. Bedford, Mark T. Arrowsmith, Cheryl H. Frye, Stephen V. |
author_sort | James, Lindsey I. |
collection | PubMed |
description | We describe the discovery of UNC1215, a potent and selective chemical probe for the methyl-lysine (Kme) reading function of L3MBTL3, a member of the malignant brain tumor (MBT) family of chromatin interacting transcriptional repressors. UNC1215 binds L3MBTL3 with a K(d) of 120 nM, competitively displacing mono- or dimethyl-lysine containing peptides, and is greater than 50-fold selective versus other members of the MBT family while also demonstrating selectivity against more than 200 other reader domains examined. X-ray crystallography identified a novel 2:2 polyvalent mode of interaction. In cells, UNC1215 is non-toxic and binds directly to L3MBTL3 via the Kme-binding pocket of the MBT domains. UNC1215 increases the cellular mobility of GFP-L3MBTL3 fusion proteins and point mutants that disrupt the Kme binding function of GFP-L3MBTL3 phenocopy the effects of UNC1215. Finally, UNC1215 demonstrates a novel Kme-dependent interaction of L3MBTL3 with BCLAF1, a protein implicated in DNA damage repair and apoptosis. |
format | Online Article Text |
id | pubmed-3577944 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-35779442013-09-01 Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain James, Lindsey I. Barsyte-Lovejoy, Dalia Zhong, Nan Krichevsky, Liubov Korboukh, Victoria K. Herold, Martin J. MacNevin, Christopher J. Norris, Jacqueline L. Sagum, Cari A. Tempel, Wolfram Marcon, Edyta Guo, Hongbo Gao, Cen Huang, Xi-Ping Duan, Shili Emili, Andrew Greenblatt, Jack F. Kireev, Dmitri B. Jin, Jian Janzen, William P. Brown, Peter J. Bedford, Mark T. Arrowsmith, Cheryl H. Frye, Stephen V. Nat Chem Biol Article We describe the discovery of UNC1215, a potent and selective chemical probe for the methyl-lysine (Kme) reading function of L3MBTL3, a member of the malignant brain tumor (MBT) family of chromatin interacting transcriptional repressors. UNC1215 binds L3MBTL3 with a K(d) of 120 nM, competitively displacing mono- or dimethyl-lysine containing peptides, and is greater than 50-fold selective versus other members of the MBT family while also demonstrating selectivity against more than 200 other reader domains examined. X-ray crystallography identified a novel 2:2 polyvalent mode of interaction. In cells, UNC1215 is non-toxic and binds directly to L3MBTL3 via the Kme-binding pocket of the MBT domains. UNC1215 increases the cellular mobility of GFP-L3MBTL3 fusion proteins and point mutants that disrupt the Kme binding function of GFP-L3MBTL3 phenocopy the effects of UNC1215. Finally, UNC1215 demonstrates a novel Kme-dependent interaction of L3MBTL3 with BCLAF1, a protein implicated in DNA damage repair and apoptosis. 2013-01-06 2013-03 /pmc/articles/PMC3577944/ /pubmed/23292653 http://dx.doi.org/10.1038/nchembio.1157 Text en Users may view, print, copy, download and 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 James, Lindsey I. Barsyte-Lovejoy, Dalia Zhong, Nan Krichevsky, Liubov Korboukh, Victoria K. Herold, Martin J. MacNevin, Christopher J. Norris, Jacqueline L. Sagum, Cari A. Tempel, Wolfram Marcon, Edyta Guo, Hongbo Gao, Cen Huang, Xi-Ping Duan, Shili Emili, Andrew Greenblatt, Jack F. Kireev, Dmitri B. Jin, Jian Janzen, William P. Brown, Peter J. Bedford, Mark T. Arrowsmith, Cheryl H. Frye, Stephen V. Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain |
title | Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain |
title_full | Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain |
title_fullStr | Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain |
title_full_unstemmed | Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain |
title_short | Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain |
title_sort | discovery of a chemical probe for the l3mbtl3 methyl-lysine reader domain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577944/ https://www.ncbi.nlm.nih.gov/pubmed/23292653 http://dx.doi.org/10.1038/nchembio.1157 |
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