Modeling the Yew Tree Tubulin and a Comparison of its Interaction with Paclitaxel to Human Tubulin

Tuszyński, Jack A.; Craddock, Travis J. A.; Mane, Jonathan Y.; Barakat, Khaled; Tseng, Chih‐Yuan; Gajewski, Melissa; Winter, Philip; Alisaraie, Laleh; Patterson, Jordan; Carpenter, Eric J.; Wang, Weiwei; Deyholos, Michael K.; Li, Linji; Sun, Xiao; Zhang, Yong; Wong, Gane Ka‐Shu

doi:10.1007/s11095-012-0829-y

Cited by 20 publications

(21 citation statements)

References 41 publications

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“…Interesting research was reported on the poor affinity of paclitaxel to tubulin derived from the yew tree (Taxus baccata), which is a producer of this cytotoxin. The analysis indicated that the paclitaxel-binding site of yew tree tubulin contains several amino acid substitutions compared to human tubulin, all of which reduce the binding affinity of paclitaxel to yew tree tubulin [112].…”

Section: Molecular Modeling and Virtual Screeningmentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.

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Section: Molecular Modeling and Virtual Screeningmentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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“…The plant alpha tubulin sequences, including that cloned from T. cuspidata in this study and that cloned from T. baccata by Tuszynski et al 24) , were aligned with that of human alpha tubulin cloned from HEK293T embryonic kidney cells in this study (Fig. S1).…”

Section: Resultsmentioning

confidence: 98%

“…The amino acid sequences of plant beta or beta-1 tubulins from H. sapiens (NP_821133.1), T. cuspidata (cloned in this study), T. baccata (WWSSB1), 24) A. thaliana (BAB10059.1), Eucalyptus grandis (ABS50665.1), G. max (NP_001239638), Gossypium hirsutum (AF487511_1), Lupinus albus (CAA49736), O. sativa (AAA66495.1), T. aestivum (AAD10487.1), and Vanilla planifolia (ADZ76155.1) were aligned using Clustal X (Fig. S2).…”

Section: Methodsmentioning

confidence: 98%

“…The amino acid sequences of plant alpha or alpha-1 tubulins from Homo sapiens (NP_006073.2), T. cuspidata (cloned in this study), Taxus baccata (WWSSA2), 24) Arabidopsis thaliana (NP_176654.1), Camellia sinensis (ABC59068.2), Daucus carota (AAG02564.1), Eleusine indica (CAA06619.1), Glycine max (NP_001237301), Hirschfeldia incana (ADW66593.1), Hordeum vulgare subsp. vulgare (AAB08791.1), Medicago truncatula (XP_003624633), Miscanthus sinensis (AFC88823.1), Oryza sativa (ADM86870.1), Populus tremuloides (AAO63781.1), and Triticum aestivum (AAD10486.1) were aligned using Clustal X (Fig.…”

Section: Methodsmentioning

confidence: 99%

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Expression of recombinant alpha and beta tubulins from the yew Taxus cuspidata and analysis of the microtubule assembly in the presence of taxol

Kudo

Abe

Ito

et al. 2014

Bioscience, Biotechnology, and Biochemistry

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Taxol was originally isolated from the yew Taxus brevifolia. Because taxol inhibits the depolymerization of microtubules, the presence of a self-resistance mechanism in Taxus spp. was hypothesized. The cloning of the cDNA for alpha and beta tubulins from Taxus cuspidata and those from the human embryonic kidney cell line HEK293T revealed that the 26Asp, 359Arg, and 361Leu residues in the human beta tubulin, which are important for taxol binding, were replaced with Glu, Trp, and Met in the beta tubulin of T. cuspidata, respectively. The microtubule assembly of the recombinant alpha and beta tubulins was monitored turbidimetrically, and the results clearly demonstrated that the microtubule from T. cuspidata is less sensitive to taxol than that from HEK293T cells. The Taxus microtubule composed of the wild-type alpha tubulin and the beta tubulin with the E26D mutation restored the sensitivity to taxol. We thus postulated that the mutation identified in the beta tubulin of T. cuspidata plays a role in the self-resistance of this species against taxol.

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“…With this limitation, molecular modelling and computer simulations can offer a comprehensive and alternative approach to understand these interactions [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] . Although there have been previous attempts to model the hPD-1/hPD-L1 and hPD-1/hPD-L2 complexes, none of these models correlated well with available experimental data.…”

Section: Research Highlightmentioning

confidence: 99%

Baby Steps Toward Modelling The Full human Programmed Death-1 (PD-1) Pathway

Ahmed

Barakat

2015

Receptor Clin Invest

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Immune checkpoints are vital elements in regulating the immune system. They preserve the immunological balance between preventing continuous activated immune responses and defending against chronic infections and cancer. Blocking the immune inhibitory checkpoints pathways recently emerged as a 'game changer' approach in cancer and antiviral immunotherapy. Modeling these pathways at the atomic level provides a key step toward rationally designing selective blockers for these pathways. Current crystal structures for the immune checkpoints are mainly not for human and are very limited in their scope of interactions. Our team has been focused on building atomistic models for these proteins, characterizing their protein-protein interactions and designing new inhibitory drugs for their activity. This article highlights our recent study on modelling the human Programmed Death-1 (hPD-1) pathway by characterizing the interactions between hPD-1 and its two human ligands. In this study, we showed that hPD1 binds differently to its two ligands. We also showed that the modes of binding for each ligand are different between mouse and human, emphasizing the limited information in current mouse crystal structures. Our findings enhanced the understanding of the receptor-ligand(s) interactions and formed a significant step toward building a full model for the whole PD1 pathway. This undoubtedly will foster the ongoing efforts to develop antibodies and small molecule drugs against this important T cell immune-regulatory mechanism.To cite this article: Marawan Ahmed, et al. Baby steps toward modelling the full human programmed Death-1 (PD-1) pathway. Receptor Clin Invest 2015; 2: e825.

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Modeling the Yew Tree Tubulin and a Comparison of its Interaction with Paclitaxel to Human Tubulin

Abstract: The yew has achieved a significant reduction of paclitaxel's affinity for its tubulin by utilizing several specific residue changes in the binding pocket for paclitaxel.

Cited by 20 publications

References 41 publications

Tubulin-interactive stilbene derivatives as anticancer agents

Tubulin-interactive stilbene derivatives as anticancer agents

Expression of recombinant alpha and beta tubulins from the yew Taxus cuspidata and analysis of the microtubule assembly in the presence of taxol

Baby Steps Toward Modelling The Full human Programmed Death-1 (PD-1) Pathway

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