Comparison of the ATP binding sites of protein kinases using conformationally diverse bisindolylmaleimides.
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 PKCalpha, PKCbeta, MSK1, p70 S6K, PDK-1, and MAPKAP-K1alpha) may be best inhibited by bisindolylmaleimides which adopt a compressed approximately C2-symmetric anti conformation; in constrast, GSK3beta 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.
Bartlett
Stephen
S
School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
Beddard
Godfrey S
GS
Jackson
Richard M
RM
Kayser
Veysel
V
Kilner
Colin
C
Leach
Andrew
A
Nelson
Adam
A
Oledzki
Peter R
PR
Parker
Peter
P
Reid
Gavin D
GD
Warriner
Stuart L
SL
D000255:Adenosine Triphosphate / Q000737:chemistry*; D001665:Binding Sites; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D011494:Protein Kinases / Q000737:chemistry* / Q000187:drug effects; D017433:Protein Structure, Secondary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007211:Indoles; D008024:Ligands; D008301:Maleimides; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C088060:bisindolylmaleimide