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| Title | An evolution-conserved allosteric network in human tubulin governs paclitaxel efficacy. |
|---|---|
| Journal, issue, pages | Nat Chem Biol, Year 2026 |
| Publish date | Apr 15, 2026 |
 Authors | Jingyi Luo / Chen Jing Khoo / Weixin Chen / Zheng Liu / Boxuan Li / Wei Sin Lau / Xiang David Li / Shih-Chieh Ti /  |
| PubMed Abstract | Tubulin-targeting agents such as paclitaxel have been a cornerstone of cancer treatment. However, the molecular basis by which prognosis-associated tubulin isotypes and mutations (that is, variants) ...Tubulin-targeting agents such as paclitaxel have been a cornerstone of cancer treatment. However, the molecular basis by which prognosis-associated tubulin isotypes and mutations (that is, variants) affect drug efficacy remains unclear. Here we reveal that evolutionarily conserved tubulin residues modulate the allosteric network to determine paclitaxel efficacy. The paclitaxel resistance of human β3-tubulin depends on a residue distant from the taxane-binding pocket. The ~2.3 Å-resolution cryo-EM microtubule reconstructions demonstrate that the paclitaxel-sensitizing tubulin mutation induces allostery at the paclitaxel-binding site, intertubulin interactions and nucleotide-binding pockets. In particular, the reoriented guanine triphosphate (GTP)-hydrolyzing catalytic α-tubulin E254 residue enhances the GTP cap, reducing the catastrophe frequency of dynamic microtubules. Examining genome-edited cancer cells with the paclitaxel-sensitized mutant β3-tubulin indicates that the affinities of tubulin variants for paclitaxel determine drug efficacy. Our findings provide mechanistic insights into the development of new tubulin-targeting therapeutics not only for cancer but also for tubulinopathies associated with mutations in specific tubulin isotypes. |
 External links | Nat Chem Biol / PubMed:41986561 |
| Methods | EM (single particle) |
| Resolution | 2.26 - 2.48 Å |
| Structure data | EMDB-65885, PDB-9wd7: EMDB-65886, PDB-9wd9: EMDB-65887, PDB-9wda: EMDB-65888, PDB-9wdb: EMDB-68133, PDB-22aj: EMDB-68134, PDB-22ak: |
| Chemicals |  ChemComp-MG:  ChemComp-GDP:  ChemComp-GTP:  ChemComp-G2P:  ChemComp-TA1: |
| Source |
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 Keywords | STRUCTURAL PROTEIN / Cytoskeleton / microtubules / human tubulin isotypes / paclitaxel |
homo sapiens (human)