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Mechanism of microtubule stabilization by taccalonolide AJ.

<div class='caption-title'>Effect of AJ on tubulin oligomerization.</div>
<div class='caption-title'>AJ covalent binding to β-tubulin.</div>
<div class='caption-title'>Possible reaction mechanisms of the ester bond between taccalonolide AJ and β-tubulin D226.</div>
Wang Y, Yu Y, Li GB, Li SA, Wu C, Gigant B, Qin W, Chen H, Wu Y, Chen Q, Yang J
OpenAccess logo Nat Commun 8 15787 (2017)
Cited: 32 times
EuropePMC logo PMID: 28585532

Abstract

As a major component of the cytoskeleton, microtubules consist of αβ-tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecular mechanisms by which MSAs stabilize microtubules remain elusive. Here we report a 2.05 Å crystal structure of tubulin complexed with taccalonolide AJ, a newly identified taxane-site MSA. Taccalonolide AJ covalently binds to β-tubulin D226. On AJ binding, the M-loop undergoes a conformational shift to facilitate tubulin polymerization. In this tubulin-AJ complex, the E-site of tubulin is occupied by GTP rather than GDP. Biochemical analyses confirm that AJ inhibits the hydrolysis of the E-site GTP. Thus, we propose that the β-tubulin E-site is locked into a GTP-preferred status by AJ binding. Our results provide experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance.

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  2. Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents. Chen X, Winstead A, Yu H, Peng J. Cancers (Basel) 13 920 (2021)

Articles - 5ezy mentioned but not cited (5)

  1. Mechanism of microtubule stabilization by taccalonolide AJ. Wang Y, Yu Y, Li GB, Li SA, Wu C, Gigant B, Qin W, Chen H, Wu Y, Chen Q, Yang J. Nat Commun 8 15787 (2017)
  2. Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands. Balaguer FA, Mühlethaler T, Estévez-Gallego J, Calvo E, Giménez-Abián JF, Risinger AL, Sorensen EJ, Vanderwal CD, Altmann KH, Mooberry SL, Steinmetz MO, Oliva MÁ, Prota AE, Díaz JF. Int J Mol Sci 20 E1392 (2019)
  3. A new microtubule-stabilizing agent shows potent antiviral effects against African swine fever virus with no cytotoxicity. Sirakanyan S, Arabyan E, Hakobyan A, Hakobyan T, Chilingaryan G, Sahakyan H, Sargsyan A, Arakelov G, Nazaryan K, Izmailyan R, Abroyan L, Karalyan Z, Arakelova E, Hakobyan E, Hovakimyan A, Serobian A, Neves M, Ferreira J, Ferreira F, Zakaryan H. Emerg Microbes Infect 10 783-796 (2021)
  4. Elucidating target specificity of the taccalonolide covalent microtubule stabilizers employing a combinatorial chemical approach. Du L, Yee SS, Ramachandran K, Risinger AL. Nat Commun 11 654 (2020)
  5. Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities. Risinger AL, Hastings SD, Du L. J Nat Prod 84 1799-1805 (2021)


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  3. Intrinsic and Extrinsic Factors Affecting Microtubule Dynamics in Normal and Cancer Cells. Borys F, Joachimiak E, Krawczyk H, Fabczak H. Molecules 25 E3705 (2020)
  4. Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target. Vicente-Blázquez A, González M, Álvarez R, Del Mazo S, Medarde M, Peláez R. Med Res Rev 39 775-830 (2019)
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  2. Structural Modification of the 3,4,5-Trimethoxyphenyl Moiety in the Tubulin Inhibitor VERU-111 Leads to Improved Antiproliferative Activities. Wang Q, Arnst KE, Wang Y, Kumar G, Ma D, Chen H, Wu Z, Yang J, White SW, Miller DD, Li W. J Med Chem 61 7877-7891 (2018)
  3. Design, Synthesis, and Biological Evaluation of Stable Colchicine-Binding Site Tubulin Inhibitors 6-Aryl-2-benzoyl-pyridines as Potential Anticancer Agents. Chen H, Deng S, Albadari N, Yun MK, Zhang S, Li Y, Ma D, Parke DN, Yang L, Seagroves TN, White SW, Miller DD, Li W. J Med Chem 64 12049-12074 (2021)
  4. Taccalonolide Microtubule Stabilizers Generated Using Semisynthesis Define the Effects of Mono Acyloxy Moieties at C-7 or C-15 and Disubstitutions at C-7 and C-25. Ola ARB, Risinger AL, Du L, Zammiello CL, Peng J, Cichewicz RH, Mooberry SL. J Nat Prod 81 579-593 (2018)
  5. Unravelling the covalent binding of zampanolide and taccalonolide AJ to a minimalist representation of a human microtubule. Sánchez-Murcia PA, Mills A, Cortés-Cabrera Á, Gago F. J Comput Aided Mol Des 33 627-644 (2019)
  6. Viriditoxin Stabilizes Microtubule Polymers in SK-OV-3 Cells and Exhibits Antimitotic and Antimetastatic Potential. Su M, Zhao C, Li D, Cao J, Ju Z, Kim E, Jung YS, Jung JH. Mar Drugs 18 E445 (2020)
  7. Colchicine Binding Site Agent DJ95 Overcomes Drug Resistance and Exhibits Antitumor Efficacy. Arnst KE, Wang Y, Lei ZN, Hwang DJ, Kumar G, Ma D, Parke DN, Chen Q, Yang J, White SW, Seagroves TN, Chen ZS, Miller DD, Li W. Mol Pharmacol 96 73-89 (2019)
  8. Identification of C-6 as a New Site for Linker Conjugation to the Taccalonolide Microtubule Stabilizers. Du L, Risinger AL, Yee SS, Ola ARB, Zammiello CL, Cichewicz RH, Mooberry SL. J Nat Prod 82 583-588 (2019)
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  12. Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma. Han J, Zhang S, Niu J, Zhang C, Dai W, Wu Y, Hu L. Molecules 25 E5586 (2020)
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  15. In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site. Takahashi-Ruiz L, Morris JD, Crews P, Johnson TA, Risinger AL. Molecules 27 4244 (2022)
  16. Measuring the linear viscoelastic regime of MCF-7 cells with a monolayer rheometer in the presence of microtubule-active anti-cancer drugs at high concentrations. Lee S, Bashir KMI, Jung DH, Basu SK, Seo G, Cho MG, Wierschem A. Interface Focus 12 20220036 (2022)
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