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 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.
Yan
Youwei
Y
Merck Research Laboratories, West Point, PA 19486, USA.
Sardana
Vinod
V
Xu
Bei
B
Homnick
Carl
C
Halczenko
Wasyl
W
Buser
Carolyn A
CA
Schaber
Michael
M
Hartman
George D
GD
Huber
Hans E
HE
Kuo
Lawrence C
LC
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*
D020409:Molecular Motor Proteins; D011743:Pyrimidines; D013871:Thiones; D000244:Adenosine Diphosphate; C400223:monastrol; D016547:Kinesins; D008274:Magnesium