Small-Molecule Ligands of Methyl-Lysine Binding Proteins

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• 作者：J. Martin Herold ; Tim J. Wigle ; Jacqueline L. Norris ; Robert Lam ; Victoria K. Korboukh ; Cen Gao ; Lindsey A. Ingerman ; Dmitri B. Kireev ; Guillermo Senisterra ; Masoud Vedadi ; Ashutosh Tripathy ; Peter J. Brown ; Cheryl H. Arrowsmith ; Jian Jin ; William P. Janzen ; Stephen V. Frye
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2504-2511
• 全文大小：967K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

Proteins which bind methylated lysines (鈥渞eaders鈥?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鈭扢BT 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.