22AK

GDP human alpha1A/beta3 microtubule

Summary for 22AK

• Entry DOI: 10.2210/pdb22ak/pdb
• EMDB information: 68134
• Descriptor: Tubulin beta-3 chain, Tubulin alpha-1A chain, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: cytoskeleton, microtubules, human tubulin isotypes, paclitaxel, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 101684.95

Authors

Ti, S.C.,Luo, J.Y.,Khoo, C.J. (deposition date: 2026-01-05, release date: 2026-04-01, Last modification date: 2026-04-29)

Primary citation

Luo, J.,Khoo, C.J.,Chen, W.,Liu, Z.,Li, B.,Lau, W.S.,Li, X.D.,Ti, S.C.
An evolution-conserved allosteric network in human tubulin governs paclitaxel efficacy.
Nat.Chem.Biol., 2026

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) 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.

PubMed: 41986561
DOI: 10.1038/s41589-026-02204-2

Experimental method

ELECTRON MICROSCOPY (2.41 Å)