An evolution-conserved allosteric network in human tubulin governs paclitaxel efficacy - PubMed
3 hours ago
- #Allostery
- #Tubulin
- #Paclitaxel
- Paclitaxel, a tubulin-targeting agent, is a cornerstone in cancer treatment, but the impact of tubulin isotypes and mutations on its efficacy was unclear.
- Researchers discovered an evolutionarily conserved allosteric network in human tubulin that determines paclitaxel efficacy, with resistance in β3-tubulin linked to a residue distant from the drug-binding pocket.
- Cryo-EM microtubule reconstructions at ~2.3 Å resolution showed that a paclitaxel-sensitizing mutation induces allosteric changes at the paclitaxel site, intertubulin interactions, and nucleotide pockets.
- The mutation reorients the GTP-hydrolyzing α-tubulin E254 residue, enhancing the GTP cap and reducing catastrophe frequency in dynamic microtubules.
- Studies in genome-edited cancer cells confirmed that tubulin variant affinities for paclitaxel determine drug efficacy, offering insights for new therapeutics in cancer and tubulinopathies.