Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures.

ABSTRACT: Bruton's tyrosine kinase (BTK) plays a key role in B cell receptor signaling and is considered a promising drug target for lymphoma and inflammatory diseases. We have determined the X-ray crystal structures of BTK kinase domain in complex with six inhibitors from distinct chemical classes. Five different BTK protein conformations are stabilized by the bound inhibitors, providing insights into the structural flexibility of the Gly-rich loop, helix C, the DFG sequence, and activation loop. The conformational changes occur independent of activation loop phosphorylation and do not correlate with the structurally unchanged WEI motif in the Src homology 2-kinase domain linker. Two novel activation loop conformations and an atypical DFG conformation are observed representing unique inactive state

SUBMITTER: Kuglstatter A 

PROVIDER: S-EPMC3048427 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature