The structure of the ternary Eg5–ADP–ispinesib complex

Talapatra, Sandeep K.; Schüttelkopf, Alexander W.; Kozielski, Frank

doi:10.1107/s0907444912027965

Cited by 45 publications

(52 citation statements)

References 44 publications

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“…6. The figure compares our new structure with previously reported structures of Eg5-ADP binary complex (PDB entry 1II6) (2) and Eg5-ADP-ispinesib ternary complex (PDB entry 4AP0) (30). Differing from the Eg5-ADP binary structure, our new structure shows loop L5 moving toward helix ␣3, resulting in the closure of the inhibitor binding pocket and the trapping of ispinesib.…”

Section: Small Molecule Inhibitors Provide Insight Into the Physiologmentioning

confidence: 63%

“…S5). Detailed descriptions of the twinning problem and subsequent solution of the problem have been documented (30). This further implies that the conformation of ispinesib cannot be a factor that distinguishes the "intermediate" and "final" states of the complex.…”

Section: Kinetics Of Ispinesibmentioning

confidence: 98%

“…The Eg5-ispinesib complex crystallizes with three molecules (subsequently named A, B, and C) in the asymmetric unit. The final model comprises residues Lys 15 30 -Lys 60 , covering the region of helix ␣0 and the greater part of the small three-stranded antiparallel ␤-sheet, are not well defined, probably due to the absence of stabilizing crystal contacts. In this region, which displays high B-factors, the majority of side chains are only tentatively built.…”

Section: Kinetics Of Ispinesibmentioning

confidence: 99%

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“Snapshots” of Ispinesib-induced Conformational Changes in the Mitotic Kinesin Eg5

Kaan

Major

Tkocz

et al. 2013

Journal of Biological Chemistry

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Section: Small Molecule Inhibitors Provide Insight Into the Physiologmentioning

confidence: 63%

Section: Kinetics Of Ispinesibmentioning

confidence: 98%

Section: Kinetics Of Ispinesibmentioning

confidence: 99%

See 1 more Smart Citation

“Snapshots” of Ispinesib-induced Conformational Changes in the Mitotic Kinesin Eg5

Kaan

Major

Tkocz

et al. 2013

Journal of Biological Chemistry

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“…Kinesin inhibition by small molecules Kinesin-5 inhibition by ispinesib Like monastrol (Cochran et al, 2005), ispinesib inhibits ADP release by kinesin-5 and slows motor binding to microtubules (Lad et al, 2008). Crystal structures show ispinesib bound to Eg5-ADP at the same induced-fit cleft near loop L5 as monastrol (Zhang et al, 2008;Talapatra et al, 2012). Superpositions show that L5 and L8, the tilted switch II helices a4 and a5, and the docked neck linker of Eg5-ADP-ispinesib are in the ATP-like conformation, resembling Eg5-ADP-monastrol.…”

Section: Myosin Activatormentioning

confidence: 99%

“…One of the most promising of the new smallmolecule inhibitors is ispinesib, which was discovered in a screen for inhibitors of human kinesin-5 Eg5 ATPase activity (Lad et al, 2008). Despite its structural differences compared with monastrol, the effects of the two compounds on Eg5 are remarkably similar -both bind specifically to Eg5 by induced fit (Lad et al, 2008;Zhang et al, 2008;Talapatra et al, 2012), stabilizing L5 in an ATP-like conformation, and both inhibit ADP release and motility (Maliga et al, 2002;Lad et al, 2008) (Box 2). Ispinesib is more potent than monastrol and is currently being evaluated in phase II clinical trials for its effectiveness in improving the outcome of different cancers (see http:// clinicaltrials.gov).…”

Section: Kinesin Inhibitorsmentioning

confidence: 99%

Force generation by kinesin and myosin cytoskeletal motor proteins

Kull

Endow

2012

Journal of Cell Science

102

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SummaryKinesins and myosins hydrolyze ATP, producing force that drives spindle assembly, vesicle transport and muscle contraction. How do motors do this? Here we discuss mechanisms of motor force transduction, based on their mechanochemical cycles and conformational changes observed in crystal structures. Distortion or twisting of the central b-sheet -proposed to trigger actininduced P i and ADP release by myosin, and microtubule-induced ADP release by kinesins -is shown in a movie depicting the transition between myosin ATP-like and nucleotide-free states. Structural changes in the switch I region form a tube that governs ATP hydrolysis and P i release by the motors, explaining the essential role of switch I in hydrolysis. Comparison of the motor power strokes reveals that each stroke begins with the force-amplifying structure oriented opposite to the direction of rotation or swing. Motors undergo changes in their mechanochemical cycles in response to small-molecule inhibitors, several of which bind to kinesins by induced fit, trapping the motors in a state that resembles a force-producing conformation. An unusual motor activator specifically increases mechanical output by cardiac myosin, potentially providing valuable information about its mechanism of function. Further study is essential to understand motor mechanochemical coupling and energy transduction, and could lead to new therapies to treat human disease. IntroductionCytoskeletal motors have been intensively studied over the past 25 years, but our understanding of how force is produced by the motors is still incomplete. The first crystal structure of a kinesin motor domain revealed an unexpected structural homology between the kinesins and myosins -the motor domain of both proteins is formed by the same core structural elements, organized in the same way to form the nucleotide-or filament-binding site on opposite sides of the motor domain. These structural elements and their organization are conserved within the kinesin and myosin superfamilies, implying a common mechanism of force generation by the motors. By contrast, the dyneins deviate in overall structure from the kinesins and myosins, and presumably also in their mechanism of energy transduction (Carter et al., 2011;Kon et al., 2011;Kon et al., 2012;Höök and Vallee, 2012;Schmidt et al., 2012). The focus of this Commentary is on the kinesins and myosins, for which more is known regarding the motor force-producing mechanism than for the dyneins. We discuss the mechanochemical cycles of the motors and the conformational changes they undergo, based on crystal structures of the motors in different nucleotide states. We propose possible force-producing mechanisms of the motors and compare their working strokes. We also discuss smallmolecule inhibitors of the kinesins and an activator of myosin, whose analysis has resulted in further insights into motor function. Further information on kinesin inhibitors can be found in a recent review (Good et al., 2011).

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Kinesin Spindle Protein (KSP) Inhibitors in Combination with Chemotherapeutic Agents for Cancer Therapy

et al. 2013

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A diverse group of proteins, the activities of which are precisely orchestrated during mitosis, have emerged as targets for cancer therapeutics; these include the Aurora kinases (AKs), Polo-like kinases (PLKs), and the kinesin spindle protein (KSP). KSP is essential for the proper separation of spindle poles during mitosis. Agents that target KSP selectively act on cells undergoing cell division, which means that KSP inhibitors are mitosis-specific drugs, and have demonstrated remarkable activities in vitro. However, a significant obstacle to the success of KSP inhibitors is that these compounds, with tremendous efficacy in vitro, have demonstrated little or even no antitumor activity in vivo. Accumulated data suggest that a combination of KSP inhibitors with various cytostatic drugs will result in a more powerful tumor-killing effect than monotherapy. Combination therapies might predominate and represent the next frontier in the discovery research of KSP inhibitors as potential anticancer drugs. Few published studies have reviewed combination therapy using KSP inhibitors. Herein we provide a comprehensive review of the literature on KSP inhibitor monotherapy and therapeutic combinations. The current state and problems are also discussed.

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The structure of the ternary Eg5–ADP–ispinesib complex

Abstract: The complex between the motor protein Eg5 and the phase II clinical candidate ispinesib provides insights into the mechanism of action of this important class of inhibitors.

Cited by 45 publications

References 44 publications

“Snapshots” of Ispinesib-induced Conformational Changes in the Mitotic Kinesin Eg5

“Snapshots” of Ispinesib-induced Conformational Changes in the Mitotic Kinesin Eg5

Force generation by kinesin and myosin cytoskeletal motor proteins

Kinesin Spindle Protein (KSP) Inhibitors in Combination with Chemotherapeutic Agents for Cancer Therapy

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