7DAF

IXA in complex with tubulin

Summary for 7DAF

• Entry DOI: 10.2210/pdb7daf/pdb
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, (1~{S},3~{S},7~{S},10~{R},11~{S},12~{S},16~{R})-8,8,10,12,16-pentamethyl-3-[(~{E})-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-7,11-bis(oxidanyl)-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione, ... (13 entities in total)
• Functional Keywords: tubulin, protein-drug complex, cell cycle
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 6
• Total formula weight: 265308.06

Authors

Wu, C.,Wang, Y. (deposition date: 2020-10-16, release date: 2021-03-24, Last modification date: 2023-11-29)

Primary citation

Xiao, Q.,Xue, T.,Shuai, W.,Wu, C.,Zhang, Z.,Zhang, T.,Zeng, S.,Sun, B.,Wang, Y.
High-resolution X-ray structure of three microtubule-stabilizing agents in complex with tubulin provide a rationale for drug design.
Biochem.Biophys.Res.Commun., 534:330-336, 2021

PubMed Abstract: Microtubule is a key component of cytoskeleton and has been considered as an important target for the treatment of cancer. In particular, the tubulin taxane-site inhibitors such as taxol analogs and epothilones have achieved great success in clinical trials. However, the structural basis of many taxane-site inhibitors is still lacking in exploring their mechanism of action. We here reported crystal complex structures for three taxane-site inhibitors, Ixabepilone, Epothilone B, and Epothilone D, which were determined to 2.4 Å, 2.4 Å, and 2.85 Å, respectively. The crystal structures revealed that these taxane-site inhibitors possess similar binding modes to that of Epothilone A at the taxane site, e.g. making critical hydrogen-bonding interactions with multiple residues on the M-loop, which facilitating the tubulin polymerization. Furthermore, we summarized the binding modes of almost all taxane-site inhibitors and identified novel taxane-site ligands with simpler chemical structures through virtual screening. On this basis, new derivatives with higher binding affinity to tubulin were designed and developed, which can form additional hydrogen bond interactions with tubulin. Overall, this work determined the mechanism of action of epothilones and provided a structural basis to design reasonably novel taxane-site inhibitors with simpler structure and improved pharmacokinetic properties.

PubMed: 33272565
DOI: 10.1016/j.bbrc.2020.11.082

Experimental method

X-RAY DIFFRACTION (2.4 Å)