1314241-41-2Relevant articles and documents
Small-molecule ligands of methyl-lysine binding proteins
Herold, J. Martin,Wigle, Tim J.,Norris, Jacqueline L.,Lam, Robert,Korboukh, Victoria K.,Gao, Cen,Ingerman, Lindsey A.,Kireev, Dmitri B.,Senisterra, Guillermo,Vedadi, Masoud,Tripathy, Ashutosh,Brown, Peter J.,Arrowsmith, Cheryl H.,Jin, Jian,Janzen, William P.,Frye, Stephen V.
, p. 2504 - 2511 (2011/06/24)
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.
