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

J Mol Biol. 2004 Jan 9;335(2):547-54. doi: 10.1016/j.jmb.2003.10.074.

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Diphosphate / chemistry
  • Adenosine Diphosphate / metabolism
  • Binding Sites
  • Crystallization
  • Crystallography, X-Ray
  • Humans
  • Kinesin / antagonists & inhibitors*
  • Kinesin / chemistry*
  • Magnesium / metabolism
  • Microtubules / chemistry
  • Mitosis
  • Models, Molecular
  • Molecular Motor Proteins
  • Protein Binding / genetics
  • Protein Conformation
  • Protein Structure, Tertiary
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Thiones / pharmacology*

Substances

  • Molecular Motor Proteins
  • Pyrimidines
  • Thiones
  • Adenosine Diphosphate
  • monastrol
  • Kinesin
  • Magnesium

Associated data

  • PDB/1Q0B