Hallmarks of Molecular Action of Microtubule Stabilizing Agents

Baine, Marina K.; Menon, Vilas; Yang, Chia Ping Huang; Northcote, Peter T.; Miller, John H.; Angeletti, Ruth Hogue; Fiser, András; Horwitz, Susan Band; Xiao, Hui

doi:10.1074/jbc.m110.162214

Cited by 60 publications

(58 citation statements)

References 51 publications

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“…The binding sites 1 and 2 are located in b-tubulin, while binding site 3 is in a-tubulin. The binding site 1 consists of b-tubulin residues Gln291, Ala296, Lys336 and Asn337, and it is basically in agreement with the alternative site previously reported 13,14 . The binding site 2 is made up of b-tubulin residues Asp224, His227, Thr274, Arg276, Arg282 and Gly360, and it just located in the well-known taxane site.…”

Section: Molecular Dockingsupporting

confidence: 77%

“…In docking mode 1, the binding site is composed of b-tubulin residues Pro287, Thr290, Gln291, Gln292, Phe294, Asp295, Ala296, Pro305, Arg306, Gln329, Asn332, Val333, Lys336, Asn337 and Tyr340. It is worth the whistle, the previous experimental study has reported that the candidate region for PLA-binding site, being called the alternative site 14 , is composed of peptides b294-301 (H9-H9 0 loop), b302-314 (H9 0 -S8) and b332-340 (H10 loop) detected by HDX-MS 13 . It is easy to find that the most key residues (Phe294, Asp295, Ala296, Pro305, Arg306, Asn332, Val333, Lys336, Asn337 and Tyr340) of the binding site 1 predicted by the docking appear in the alternative site.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…As a matter of fact, the PLA-binding site proposed by Huzil et al is also called the alternative site. Recently, Nguyen et al proposed that PLA was equally likely to bind in the taxane site and the alternative site in b-tubulin 14 . In the researches for PLA, some pivotal progress has been made through experimental methods; however, so far the exact binding site of PLA has not been accurately identified yet and in particular, the knowledge on how it binds to tubulin at a molecular level is still insufficient.…”

Section: Introductionmentioning

confidence: 99%

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Docking and molecular dynamics studies of the binding between Peloruside A and tubulin

Liao

Chen

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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The molecular docking, MD simulation and binding free energy calculation were performed to explore the probable binding modes between PLA and tubulin. Through docking study, three possible binding sites for PLA were speculated as follows: the taxane site, the alternative site and a new site in a-tubulin. Then, 12.0 ns MD simulations show that these binding modes predicted by docking have been changed more or less, whereas the MD simulations offer more reliable binding details. The MM-PBSA binding free-energy calculations reasonably identify that the taxane site is the most favorable binding site of PLA and the alternative site is the secondary one, which can be used to explain some experimental facts. These studies theoretically resolve the priority of binding sites for PLA and offer the reliable binding modes between PLA and tubulin, and thus help to understanding the action mechanism for this kind of inhibitor.

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Section: Molecular Dockingsupporting

confidence: 77%

Section: Molecular Dockingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Docking and molecular dynamics studies of the binding between Peloruside A and tubulin

Liao

Chen

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Drug binding and suppression of microtubule dynamic instability also impair many interphase functions of microtubules including migration, intracellular trafficking, and cell secretion [11][12][13]. Several studies have briefly reported some of ixabepilone's properties in cells [14,15] and in vitro [7][8][9], but there has been no full elucidation of its mechanism of action including its response to altered tubulin isotype expression.…”

Section: Introductionmentioning

confidence: 99%

“…At least seven isotypes of β-tubulin are expressed differently in different cell types [6], but their cellular roles are poorly understood. Like taxanes, ixabepilone binds to microtubules [7], enhances their assembly [8], and stabilizes them against disassembly, and preliminary data suggested that it suppressed dynamic instability [9]. Dynamic instability is a microtubule behavior that involves transitions between slow growth and rapid shortening of individual microtubules [10].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of action of ixabepilone and its interactions with the βIII-tubulin isotype

Lopus

Smiyun

Miller

et al. 2015

Cancer Chemother Pharmacol

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Ixabepilone (Ixempra, BMS-247550), a semisynthetic analog of epothilone B, is a microtubule-targeted drug in clinical use for treatment of metastatic or locally advanced breast cancer. Ixabepilone's binding and mechanism of action on microtubules and their dynamics, as well as its interactions with isotypically altered microtubules, both in vitro and in tumor cells, have not been described. Microtubules are dynamic polymers of the protein tubulin that function in mitosis, intracellular transport, cell proliferation, and migration. They continually undergo dynamic instability, periods of slow growth and rapid shortening that are crucial to these cell functions. We determined ixabepilone's microtubule binding and polymerization effects in vitro and also determined its effects on inhibition of dynamic instability in vitro and in cells, both with and without removal of the βIII isotype of tubulin. The βIII isotype of tubulin is associated with drug resistance and tumor aggressivity. We found that removal (in vitro) and knockdown (in cells) of βIII-tubulin led to increased inhibition of microtubule dynamic instability by ixabepilone. Depletion of βIII-tubulin from MCF7 human breast cancer cells also induced increased mitotic arrest by ixabepilone. Thus, βIII-tubulin expression suppresses the antitumor effects of ixabepilone, indicating that increased βIII-tubulin may be an important contributor to the development of resistance to ixabepilone.

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Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A

et al. 2014

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Laulimalide and peloruside A are microtubule‐stabilizing agents (MSAs), the mechanism of action on microtubules of which is poorly defined. Here, using X‐ray crystallography it is shown that laulimalide and peloruside A bind to a unique non‐taxane site on β‐tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. At the same time, they allosterically stabilize the taxane‐site M‐loop that establishes lateral tubulin contacts in microtubules. Structures of ternary complexes of tubulin with laulimalide/peloruside A and epothilone A are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M‐loop of β‐tubulin is found. Together, the data define the mechanism of action of laulimalide and peloruside A on tubulin and microtubules. The data further provide a structural framework for understanding the synergy observed between two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth.

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Hallmarks of Molecular Action of Microtubule Stabilizing Agents

Cited by 60 publications

References 51 publications

Docking and molecular dynamics studies of the binding between Peloruside A and tubulin

Docking and molecular dynamics studies of the binding between Peloruside A and tubulin

Mechanism of action of ixabepilone and its interactions with the βIII-tubulin isotype

Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A

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