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 displ...
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| Veröffentlicht in: | Nature chemical biology 2013-01, Vol.9 (3), p.184-191 |
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| creator | 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. |
| 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. |
| doi_str_mv | 10.1038/nchembio.1157 |
| format | Article |
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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.</description><identifier>ISSN: 1552-4450</identifier><identifier>EISSN: 1552-4469</identifier><identifier>DOI: 10.1038/nchembio.1157</identifier><identifier>PMID: 23292653</identifier><language>eng</language><ispartof>Nature chemical biology, 2013-01, Vol.9 (3), p.184-191</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids></links><search><creatorcontrib>James, Lindsey I.</creatorcontrib><creatorcontrib>Barsyte-Lovejoy, Dalia</creatorcontrib><creatorcontrib>Zhong, Nan</creatorcontrib><creatorcontrib>Krichevsky, Liubov</creatorcontrib><creatorcontrib>Korboukh, Victoria K.</creatorcontrib><creatorcontrib>Herold, Martin J.</creatorcontrib><creatorcontrib>MacNevin, Christopher J.</creatorcontrib><creatorcontrib>Norris, Jacqueline L.</creatorcontrib><creatorcontrib>Sagum, Cari A.</creatorcontrib><creatorcontrib>Tempel, Wolfram</creatorcontrib><creatorcontrib>Marcon, Edyta</creatorcontrib><creatorcontrib>Guo, Hongbo</creatorcontrib><creatorcontrib>Gao, Cen</creatorcontrib><creatorcontrib>Huang, Xi-Ping</creatorcontrib><creatorcontrib>Duan, Shili</creatorcontrib><creatorcontrib>Emili, Andrew</creatorcontrib><creatorcontrib>Greenblatt, Jack F.</creatorcontrib><creatorcontrib>Kireev, Dmitri B.</creatorcontrib><creatorcontrib>Jin, Jian</creatorcontrib><creatorcontrib>Janzen, William P.</creatorcontrib><creatorcontrib>Brown, Peter J.</creatorcontrib><creatorcontrib>Bedford, Mark T.</creatorcontrib><creatorcontrib>Arrowsmith, Cheryl H.</creatorcontrib><creatorcontrib>Frye, Stephen V.</creatorcontrib><title>Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain</title><title>Nature chemical biology</title><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.</description><issn>1552-4450</issn><issn>1552-4469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNqljE9rwjAcQINM1DmPu_--QDVpmtZednBzTHA37yFtf10j-VOSKvTbj4EInnd6Dx48Ql4ZXTPKtxtXd2gr7deMiWJCFkyINMmyvHy6u6Bz8hzjmVKe52w7I_OUp2WaC74ghw8da3_FMIJvQcHfTdfKQB98hdD6AEOHcOTfu9ORg8WhG01ixqgdQkDVYIDGW6XdC5m2ykRc3bgkb5_70_tX0l8qi02NbgjKyD5oq8IovdLysTjdyR9_lVwURZll_N-DX1-3W2k</recordid><startdate>20130106</startdate><enddate>20130106</enddate><creator>James, Lindsey I.</creator><creator>Barsyte-Lovejoy, Dalia</creator><creator>Zhong, Nan</creator><creator>Krichevsky, Liubov</creator><creator>Korboukh, Victoria K.</creator><creator>Herold, Martin J.</creator><creator>MacNevin, Christopher J.</creator><creator>Norris, Jacqueline L.</creator><creator>Sagum, Cari A.</creator><creator>Tempel, Wolfram</creator><creator>Marcon, Edyta</creator><creator>Guo, Hongbo</creator><creator>Gao, Cen</creator><creator>Huang, Xi-Ping</creator><creator>Duan, Shili</creator><creator>Emili, Andrew</creator><creator>Greenblatt, Jack F.</creator><creator>Kireev, Dmitri B.</creator><creator>Jin, Jian</creator><creator>Janzen, William P.</creator><creator>Brown, Peter J.</creator><creator>Bedford, Mark T.</creator><creator>Arrowsmith, Cheryl H.</creator><creator>Frye, Stephen V.</creator><scope>5PM</scope></search><sort><creationdate>20130106</creationdate><title>Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain</title><author>James, Lindsey I. ; 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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.</abstract><pmid>23292653</pmid><doi>10.1038/nchembio.1157</doi><oa>free_for_read</oa></addata></record> |
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| title | Discovery of a chemical probe for the L3MBTL3 methyl-lysine reader domain |
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