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Insights into the Molecular Mechanisms of Eg5 Inhibition by (+)-Morelloflavone
http://hdl.handle.net/10069/39385
http://hdl.handle.net/10069/39385c63284f3-02c7-46ec-8baa-412f32c53384
名前 / ファイル | ライセンス | アクション |
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Pharma12_58.pdf (5.0 MB)
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Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2019-08-22 | |||||
タイトル | ||||||
タイトル | Insights into the Molecular Mechanisms of Eg5 Inhibition by (+)-Morelloflavone | |||||
言語 | ||||||
言語 | eng | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | (+)-morelloflavone | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Biflavonoid | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Inhibitors | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Kinesin Eg5 | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Molecular dynamics | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者 |
Ogunwa, Tomisin Happy
× Ogunwa, Tomisin Happy× Laudadio, Emiliano× Galeazzi, Roberta× Miyanishi, Takayuki |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | (+)-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. | |||||
書誌情報 |
Pharmaceuticals 巻 12, 号 2, p. 58, 発行日 2019-04-16 |
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出版者 | ||||||
出版者 | MDPI | |||||
EISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 14248247 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | 10.3390/ph12020058 | |||||
権利 | ||||||
権利情報 | c 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
引用 | ||||||
内容記述タイプ | Other | |||||
内容記述 | Pharmaceuticals, 12(2), art.no.58; 2019 |