期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 7, 页码 2504-2511出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm200045v
关键词
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资金
- NIH [RC1GM090732]
- Canadian Institutes for Health Research [1097737]
- Canada Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GkaxoSmithKline, Karolinska Institute
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation, Merck 8
- Co. Inc.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
Proteins which bind methylated lysines (readers of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a repressed transcriptional state. Antagonists of MBT domains would serve as probes to interrogate the functional role of these proteins and initiate the chemical biology of methyl-lysine readers as a target class. Small-molecule MBT antagonists were designed based on the structure of histone peptide - MBT complexes and their interaction with MBT domains determined using a chemiluminescent assay and ITC. The ligands discovered antagonize native histone peptide binding, exhibiting 5-fold stronger binding affinity to L3MBTL1 than its preferred histone peptide. The first cocrystal structure of a small molecule bound to L3MBTL1 was determined and provides new insights into binding requirements for further ligand design.
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