5EZY

Crystal structure of T2R-TTL-taccalonolide AJ complex

Summary for 5EZY

• Entry DOI: 10.2210/pdb5ezy/pdb
• Descriptor: Tubulin alpha-1B chain, taccalonolide AJ, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: tubulin, complex, inhibitor, structural protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm, cytoskeleton: Q2XVP4 Q6B856; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 265748.22

Authors

Wang, Y.,Yu, Y.,Chen, Q.,Yang, J. (deposition date: 2015-11-27, release date: 2017-01-11, Last modification date: 2023-11-08)

Primary citation

Wang, Y.,Yu, Y.,Li, G.B.,Li, S.A.,Wu, C.,Gigant, B.,Qin, W.,Chen, H.,Wu, Y.,Chen, Q.,Yang, J.
Mechanism of microtubule stabilization by taccalonolide AJ
Nat Commun, 8:15787-15787, 2017

PubMed Abstract: As a major component of the cytoskeleton, microtubules consist of αβ-tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecular mechanisms by which MSAs stabilize microtubules remain elusive. Here we report a 2.05 Å crystal structure of tubulin complexed with taccalonolide AJ, a newly identified taxane-site MSA. Taccalonolide AJ covalently binds to β-tubulin D226. On AJ binding, the M-loop undergoes a conformational shift to facilitate tubulin polymerization. In this tubulin-AJ complex, the E-site of tubulin is occupied by GTP rather than GDP. Biochemical analyses confirm that AJ inhibits the hydrolysis of the E-site GTP. Thus, we propose that the β-tubulin E-site is locked into a GTP-preferred status by AJ binding. Our results provide experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance.

PubMed: 28585532
DOI: 10.1038/ncomms15787

Experimental method

X-RAY DIFFRACTION (2.05 Å)