Comparison of the ATP binding sites of protein kinases using conformationally diverse bisindolylmaleimides

Stephen Bartlett, Godfrey S. Beddard, Richard M. Jackson, Veysel Kayser, Colin Kilner, Andrew Leach, Adam Nelson, Peter R. Oledzki, Peter Parker, Gavin D. Reid, Stuart L. Warriner

Research output: Contribution to journalArticlepeer-review


The conformation of a bisindolylmaleimide may be controlled by the size of a macrocyclic ring in which it is constrained. A range of techniques were used to demonstrate that the tether controls both the ratio of the two limiting conformers (syn and anti) in solution and the extent of conjugation between the maleimide and indole rings. Screening the conformationally diverse bisindolylmaleimides against a panel of protein kinases allowed their ATP binding sites to be compared using a chemical approach which, like sequence alignment, does not require detailed structural information. This approach lead to the conclusion that several AGC group protein kinases (including PKCα, PKCβ, MSK1, p70 S6K, PDK-1, and MAPKAP-K1α) may be best inhibited by bisindolylmaleimides which adopt a compressed approximately C 2-symmetric anti conformation; in constrast, GSK3β may be best inhibited by bisindolylmaleimides whose ground state is a distorted syn conformation. It is concluded that PDK-1, whose structure has been determined by X-ray crystallography, and its mutants, may serve as particularly useful surrogates for the study of PKC inhibitors.

Original languageEnglish
Pages (from-to)11699-11708
Number of pages10
JournalJournal of the American Chemical Society
Issue number33
Publication statusPublished - 24 Aug 2005


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