Inhibition of a mitotic motor protein: Where, how, and conformational consequences

We report here the first inhibitor-bound structure of a mitotic motor protein. The 1.9 Angstrom 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 A 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. (C) 2003 Elsevier Ltd. All rights reserved.