Nature chemical biology, 2013-03, Vol.9 (3), p.184
- James, Lindsey I
- Barsyte-Lovejoy, Dalia
- Zhong, Nan
- Krichevsky, Liubov
- Korboukh, Victoria K
- Herold, J Martin
- 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
2013
Details
- Autor(en) / Beteiligte
- James, Lindsey I
- Barsyte-Lovejoy, Dalia
- Zhong, Nan
- Krichevsky, Liubov
- Korboukh, Victoria K
- Herold, J Martin
- 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
- Titel
- Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain
- Ist Teil von
- Nature chemical biology, 2013-03, Vol.9 (3), p.184
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- We describe the discovery of UNC1215, a potent and selective chemical probe for the methyllysine (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 dimethyllysine-containing peptides, and is greater than 50-fold more potent toward L3MBTL3 than other members of the MBT family while also demonstrating selectivity against more than 200 other reader domains examined. X-ray crystallography identified a unique 2:2 polyvalent mode of interaction between UNC1215 and L3MBTL3. In cells, UNC1215 is nontoxic and directly binds 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 on localization. Finally, UNC1215 was used to reveal a new Kme-dependent interaction of L3MBTL3 with BCLAF1, a protein implicated in DNA damage repair and apoptosis.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 1552-4469DOI: 10.1038/NCHEMBIO.1157Titel-ID: cdi_pubmed_primary_23292653
- Format
- –
- Schlagworte
- Benzamides - chemistry, Benzamides - metabolism, Benzamides - pharmacology, Binding, Competitive - drug effects, Crystallography, X-Ray, DNA-Binding Proteins - antagonists & inhibitors, DNA-Binding Proteins - chemistry, DNA-Binding Proteins - metabolism, Dose-Response Relationship, Drug, Drug Discovery, HEK293 Cells, Humans, Lysine - analogs & derivatives, Lysine - antagonists & inhibitors, Lysine - chemistry, Lysine - metabolism, Models, Molecular, Molecular Probes - chemistry, Molecular Probes - metabolism, Molecular Probes - pharmacology, Molecular Structure, Piperidines - chemistry, Piperidines - metabolism, Piperidines - pharmacology, Protein Structure, Tertiary, Repressor Proteins - metabolism, Structure-Activity Relationship, Tumor Suppressor Proteins - metabolism