Kinesin-5 mitotic motors: Is loop5 the on/off switch?

Moores, Carolyn A.

doi:10.4161/cc.9.7.11144

Cited by 6 publications

(1 citation statement)

References 31 publications

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“…Inhibitors that bind at the allosteric site, i.e., the hydrophobic loop5/α2/α3 pocket, are more preferable owing to their affinity and specificity [22,23,24]. The presence of an elongated loop5 [25]—a peculiar feature of Eg5—confers selectivity and suggests lower toxicity of inhibitors that bind the allosteric loop5/α2/α3 pocket in Eg5. Therefore, researchers have focused on this binding pocket with the aim to design or identify new Eg5 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Insights into the Molecular Mechanisms of Eg5 Inhibition by (+)-Morelloflavone

et al. 2019

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(+)-Morelloflavone (MF) is an antitumor biflavonoid that is found in the Garcinia species. Recently, we reported MF as a novel inhibitor of ATPase and microtubules-gliding activities of the kinesin spindle protein (Eg5) in vitro. Herein, we provide dynamical insights into the inhibitory mechanisms of MF against Eg5, which involves binding of the inhibitor to the loop5/α2/α3 allosteric pocket. Molecular dynamics simulations were carried out for 100 ns on eight complexes: Eg5-Adenosine diphosphate (Eg5-ADP), Eg5-ADP-S-trityl-l-cysteine (Eg5-ADP-STLC), Eg5-ADP-ispinesib, Eg5-ADP-MF, Eg5-Adenosine triphosphate (Eg5-ATP), Eg5-ATP-STLC, Eg5-ATP-ispinesib, and Eg5-ATP-MF complexes. Structural and energetic analyses were done using Umbrella sampling, Molecular Mechanics Poisson–Boltzmann Surface Area (MM/PBSA) method, GROMACS analysis toolkit, and virtual molecular dynamics (VMD) utilities. The results were compared with those of the known Eg5 inhibitors; ispinesib, and STLC. Our data strongly support a stable Eg5-MF complex, with significantly low binding energy and reduced flexibility of Eg5 in some regions, including loop5 and switch I. Furthermore, the loop5 Trp127 was trapped in a downward position to keep the allosteric pocket of Eg5 in the so-called “closed conformation”, comparable to observations for STLC. Altered structural conformations were also visible within various regions of Eg5, including switch I, switch II, α2/α3 helices, and the tubulin-binding region, indicating that MF might induce modifications in the Eg5 structure to compromise its ATP/ADP binding and conversion process as well as its interaction with microtubules. The described mechanisms are crucial for understanding Eg5 inhibition by MF.

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