7EN3

Crystal structure of tubulin in complex with Tubulysin analogue TGL

Summary for 7EN3

• Entry DOI: 10.2210/pdb7en3/pdb
• Descriptor: Tubulin alpha-1B chain, (2S,4R)-5-(4-fluorophenyl)-2-methyl-4-[[2-[(1R,3R)-4-methyl-3-[5-methylhexyl-[(2S,3S)-3-methyl-2-[[(2R)-1-methylpiperidin-2-yl]carbonylamino]pentanoyl]amino]-1-oxidanyl-pentyl]-1,3-thiazol-4-yl]carbonylamino]pentanoic acid, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: microtubule assembly inhibitors, structural protein-inhibitor complex, structural protein/inhibitor
• Biological source: Sus scrofa (Pig); More
• Total number of polymer chains: 6
• Total formula weight: 265622.38

Authors

Wang, Y.,Li, W. (deposition date: 2021-04-15, release date: 2022-04-27, Last modification date: 2023-11-29)

Primary citation

Li, W.,Tan, L.,Zhang, Z.,Xia, Q.,Lei, D.,Li, Y.,Zhang, T.,Zeng, S.,Sima, X.,Wang, Y.
The X-ray structure of tubulysin analogue TGL in complex with tubulin and three possible routes for the development of next-generation tubulysin analogues.
Biochem.Biophys.Res.Commun., 565:29-35, 2021

PubMed Abstract: Microtubule-targeting agents (MTAs) are the most commonly used anti-cancer drugs. At least fourteen microtubule inhibitors and ten antibody drug conjugates (ADCs) linking MTAs are approved by FDA for clinical use in cancer therapy. In current research, we determined the crystal structure of tubulysin analogue TGL in complex with tubulin at a high resolution (2.65 Å). In addition, we summarized all of the previously published high-resolution crystal structures of ligands in the vinca site to provide structural insights for the rational design of the new vinca-site ligands. Moreover, based on the aligned results of the vinca site ligands, we provided three possible routes for designing new tubulysin analogues, namely macrocyclization between the N-14 side chain and the N-9 side chain, the hybird of tubulysin M and phomopsin A, and growing new aryl group at C-21. These designed structures will inspire the development of new MTAs or payloads in cancer therapy.

PubMed: 34090207
DOI: 10.1016/j.bbrc.2021.05.086

Experimental method

X-RAY DIFFRACTION (2.643 Å)