期刊
NATURE CHEMICAL BIOLOGY
卷 9, 期 3, 页码 184-191出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1157
关键词
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资金
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- US National Institute of General Medical Sciences
- US National Institutes of Health [RC1GM090732, R01GM100919]
- Carolina Partnership
- University Cancer Research Fund
- University of North Carolina at Chapel Hill
- Center for Environmental and Molecular Carcinogenesis at the M.D. Anderson Cancer Center
- National Institute of Mental Health Psychoactive Drug Screening Program
- Ontario Research Fund [ORF-GL2]
- Natural Sciences and Engineering Research Council of Canada
- Ontario Ministry of Health and Long-Term Care
- American Cancer Society [119169-PF-10-183-01-TBE]
- Structural Genomics Consortium
- Canadian Institutes of Health Research [1097737]
- Eli Lilly Canada
- Genome Canada
- GlaxoSmithKline
- Ontario Ministry of Economic Development and Innovation
- Novartis Research Foundation
- Pfizer
- Abbott
- Takeda
- Wellcome Trust
- US National Institute of Environmental Health Sciences [ES007784]
- Cancer Prevention Research Institute of Texas [RP110471]
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.
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