Inhibition of a Mitotic Motor Protein: Where, How, and Conformational Consequences

Abstract

We report here the first inhibitor-bound structure of a mitotic motor protein. The 1.9 Å resolution structure of the motor domain of KSP, bound with the small molecule monastrol and Mg 2+·ADP, reveals that monastrol confers inhibition by “induced-fitting” onto the protein some 12 Å away from the catalytic center of the enzyme, resulting in the creation of a previously non-existing binding pocket. The structure provides new insights into the biochemical and mechanical mechanisms of the mitotic motor domain. Inhibition of KSP provides a novel mechanism to arrest mitotic spindle formation, a target of several approved and investigative anti-cancer agents. The structural information gleaned from this novel pocket offers a new angle for the design of anti-mitotic agents.