Small-molecule and mutational analysis of allosteric Eg5 inhibition by monastrol.

ABSTRACT:

Background

A recent crystal structure of monastrol in a ternary complex with the kinesin Eg5 motor domain highlights a novel, induced-fit drug binding site at atomic resolution. Mutational obliteration of the monastrol binding site results in a monastrol-resistant, but otherwise catalytically active Eg5 motor domain. However, considering the conformational changes at this site, it is unclear what specific interactions stabilize the interaction between monastrol and the Eg5 motor domain.

Results

To study the molecular complementarity of the monastrol-Eg5 interaction, we used a combination of synthetic chemistry and targeted mutations in Eg5 to measure the contribution of specific contacts to inhibition of Eg5 in vitro and in cultured cells. Structure-activity data on chemical

SUBMITTER: Maliga Z 

PROVIDER: S-EPMC1448180 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature