title: 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 A resolution structure of the motor domain of KSP, bound with the small molecule monastrol and Mg2+ x 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.
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Vinod
authors.initials: V
authors.lastname: Sardana
authors.forename: Bei
authors.initials: B
authors.lastname: Xu
authors.forename: Carl
authors.initials: C
authors.lastname: Homnick
authors.forename: Wasyl
authors.initials: W
authors.lastname: Halczenko
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Michael
authors.initials: M
authors.lastname: Schaber
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008274:Magnesium / Q000378:metabolism; D008870:Microtubules / Q000737:chemistry; D008938:Mitosis; D008958:Models, Molecular; D020409:Molecular Motor Proteins; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013871:Thiones / Q000494:pharmacology*
chemical_list: D020409:Molecular Motor Proteins; D011743:Pyrimidines; D013871:Thiones; D000244:Adenosine Diphosphate; C400223:monastrol; D016547:Kinesins; D008274:Magnesium