High-resolution X-ray structure of three microtubule-stabilizing agents in complex with tubulin provide a rationale for drug design

Xiao, Qi; Xue, Ting; Wen, Shuai; Wu, Chengyong; Zhang, Zhixiong; Zhang, Ting; Zeng, Shaoxue; Sun, Binyong; Wang, Yuxi

doi:10.1016/j.bbrc.2020.11.082

Cited by 11 publications

(16 citation statements)

References 25 publications

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“…The peptides' binding to drugs was assessed using a molecular docking method. Seventeen MT-binding agents were studied that included paclitaxel (PTX), 37 docetaxel, 38 taccalonolide, 39 epothilones (i.e., A, B, D, and ixabepilone), 40,41 cyclostreptin, 42 dictyostatin, 43 discodermolide, 44 zampanolide, 45 and dolastatin. 51 The crystal structures of the drugs bound to α-β tubulin heterodimer exhibit they all are bound to at least one amino acid in the M-loop of β-tubulin.…”

Section: Antimitotics Bindingmentioning

confidence: 99%

“…36 The drugs act either as an MT polymerizer or depolymerizer, inhibiting its dynamic assembly-disassembly (i.e., polymerizationdepolymerization) process, essential for maintaining the cell structure and survival. There are several binding sites on the α-, β-tubulin, located at the lateral or longitudinal interface of the two tubulin monomers that could accommodate several antimitotics, such as paclitaxel, 37 docetaxel, 38 taccalonolide, 39 epothilones (types A, B, D, and ixabepilone), 40,41 cyclostreptin, 42 dictyostatin, 43 discodermolide, 44 zampanolide, 45 laulimalide, 46,47 peloruside A, 46,47 vinblastine, [48][49][50] dolastatin, 51 phomopsin A, 52 and eribulin. 53 Earlier in vivo studies have suggested that MWCNTs mimic some of the MT's properties in HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

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Microtubule-inspired functionalization of carbon nanotubes: a biomimetic carrier design

Barcelos

Alisaraie

2022

Mol. Syst. Des. Eng.

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Section: Antimitotics Bindingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Microtubule-inspired functionalization of carbon nanotubes: a biomimetic carrier design

Barcelos

Alisaraie

2022

Mol. Syst. Des. Eng.

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“…paclitaxel 37 , docetaxel 38 , taccalonolide 39 , epothilones (types A, B, D, and ixabepilone) 40,41 , cyclostreptin 42 , dictyostatin 43 , discodermolide 44 , zampanolide 45 , laulimalide, peloruside A 46 , vinblastine 48,49 , dolastatin 51 , phomopsin A 52 , and eribulin 53 . The structure of each drug was energy minimized using the steepest descent algorithm and the Tripos force field with an energy gradient ranging from 0.0005 kJ/mol to 1 kJ/mol for up to 10,000,000 iterations.…”

Section: Drugs' Structure and Binding To Peptidesmentioning

confidence: 99%

“…The peptides' binding to drugs was assessed using a molecular docking method. Seventeen MT-binding agents were studied that included paclitaxel (PTX) 37 , docetaxel 38 , taccalonolide 39 , epothilones (i.e., A, B, D, and ixabepilone) 40,41 , cyclostreptin 42 , dictyostatin 43 , discodermolide 44 , zampanolide 45 , and dolastatin. 51 The crystal structures of the drugs bound to α-β tubulin heterodimer exhibit they all are bound to at least one amino acid in the M-loop of β-tubulin.…”

Section: Antimitotics Bindingmentioning

confidence: 99%

“…36 The drugs act either as an MT polymerizer or depolymerizer, inhibiting its dynamic assembly-disassembly (i.e., polymerization-depolymerization) process, essential for maintaining the cell structure and survival. There are several binding sites on the α-, β-tubulin, located at the lateral or longitudinal interface of the two tubulin monomers that could accommodate several antimitotics, such as paclitaxel 37 , docetaxel 38 , taccalonolide 39 , epothilones (types A, B, D, and ixabepilone) 40,41 , cyclostreptin 42 , dictyostatin 43 , discodermolide 44 , zampanolide 45 , laulimalide 46,47 , peloruside A 46,47 , vinblastine [48][49][50] , dolastatin 51 , phomopsin A 52 , and eribulin 53 .…”

Section: Introductionmentioning

confidence: 99%

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Microtubule-Inspired Functionalization of Carbon Nanotubes: A Biomimetic Carrier Design

Barcelos

Alisaraie

2022

Preprint

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We propose a bioinspired, non-covalent carbon nanotubes (CNTs) functionalization strategy to augment their bioavailability and alleviate their biotoxicity. For functionalization, select amphiphilic peptides from a cytoskeletal biopolymer, microtubule (MT), were used. The peptides are involved in the MT polymerization by maintaining the essential lateral interactions among the MT's alpha- and beta-tubulin subunits. They also participate in forming the MT-binding sites for hosting several MT-targeting antimitotics. Utilizing in silico methods, this study showed the peptides influenced CNT's diffusivity and aqueous solubility. The hydrodynamic shield formed by the peptides from beta-tubulin was more widespread on the CNT than the alpha-tubulin peptides'; however, the latter created a broader hydrophobic CNT coating than those from beta-tubulin. In particular, the peptides consisting of the H1-B2, H10, H1-B2, and the M-loop, demonstrated structural features that serve to augment CNTs' water solubility and dispersibility. The performance of the peptide-functionalized CNTs as drug carriers was examined by studying seventeen antimitotics. The CNT-peptides structural composition was identified as a suitable carrier for phomopsin A, laulimalide, epothilone A, epothilone D, discodermolide, eribulin, and docetaxel. The peptides played dual roles displaying affinities to the antimitotics and the CNT; in particular, the peptides from the H1-B2 and H2-B3 loops of β-tubulin exhibited exceptional binding properties. Specific mutations on the wildtype peptides, including those from the alpha-tubulin M-loop and H2-B3, or the beta-tubulin H1-B2, are proposed to refine their hydrophobicity, eliminate unfavorable inter-peptides electrostatic interactions or the spatial hindrance at certain regions, to enhance their conformational steadiness and exposure to the tube surface. A combination of the select amphiphilic peptides from both tubulin subunits is suggested to improve CNTs bioavailability and efficiency for carrying insoluble hydrophobic cargos.

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Microtubule‐targeting agents for cancer treatment: Seven binding sites and three strategies

Wang,

Gigant,

Zheng

et al. 2023

MedComm – Oncology

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Microtubules are pivotal in diverse cellular functions encompassing cell signaling, morphology, intracellular trafficking, and cell mitosis/division. They are validated targets for disease treatment, notably hematological cancers and solid tumors. Microtubule‐targeting agents (MTAs) exert their effects by modulating microtubule dynamics, impeding cell proliferation, and promoting cell death. Recent advances in structural biology have unveiled novel perspectives for investigating multiple binding sites and mechanisms of action used by MTAs. In this review, we first provide an overview of the intricate structure and dynamics of microtubules. Then we explore the seven binding sites and the three primary strategies (stabilization, destabilization, and degradation) harnessed by MTAs. Furthermore, we introduce the emerging domain of microtubule‐targeting degraders, exemplified by PROteolysis TArgeting Chimeras and small‐molecule degraders, which enable precise degradation of specific microtubule‐associated proteins implicated in cancer pathogenesis. Additionally, we discuss the promising realm of precision‐targeted approaches, including antibody–drug conjugates and the utilization of photopharmacology in MTAs. Lastly, we provide a comprehensive overview of the clinical applications of microtubule‐targeting therapies, assessing their efficacy and current challenges. We aim to provide a global picture of MTAs development as well as insights into the microtubule‐targeting drug discovery for cancer treatment.

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High-resolution X-ray structure of three microtubule-stabilizing agents in complex with tubulin provide a rationale for drug design

Cited by 11 publications

References 25 publications

Microtubule-inspired functionalization of carbon nanotubes: a biomimetic carrier design

Microtubule-inspired functionalization of carbon nanotubes: a biomimetic carrier design

Microtubule-Inspired Functionalization of Carbon Nanotubes: A Biomimetic Carrier Design

Microtubule‐targeting agents for cancer treatment: Seven binding sites and three strategies

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