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"Snapshots" of Ispinesib-Induced Conformational Changes in the Mitotic Kinesin Eg5

DOI: 10.1074/jbc.M113.462648 DOI Help
PMID: 23658017 PMID Help

Authors: Hung Yi Kristal Kaan (Beatson Institute for Cancer Research) , Jennifer Major (Lerner Research Institute) , Katarzyna Tkocz (Beatson Institute for Cancer Research) , Frank Kozielski (Beatson Institute for Cancer Research) , Steven S. Rosenfeld (Lerner Research Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: May 2013

Abstract: Kinesins comprise a superfamily of molecular motors that drive a wide variety of cellular physiologies, from cytoplasmic transport to formation of the bipolar spindle in mitosis. These differing roles are reflected in corresponding polymorphisms in key kinesin structural elements. One of these is a unique loop and stem motif found in all kinesins and referred to as loop 5 (L5). This loop is longest in the mitotic kinesin Eg5 and is the target for a number of small molecule inhibitors, including ispinesib, which is being used in clinical trials in patients with cancer. In this study, we have used x-ray crystallography to identify a new structure of an Eg5-ispinesib complex and have combined this with transient state kinetics to identify a plausible sequence of conformational changes that occur in response to ispinesib binding. Our results demonstrate that ispinesib-induced structural changes in L5 from Eg5 lead to subsequent changes in the conformation of the switch II loop and helix and in the neck linker. We conclude that L5 in Eg5 simultaneously regulates the structure of both the ATP binding site and the motor's mechanical elements that generate force.

Journal Keywords: Benzamides; Binding; Biocatalysis; Crystallography; X-Ray; Humans; Kinesin; Kinetics; Mitosis; Models; Molecular; Protein; Secondary; Protein; Tertiary; Quinazolines

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography