7E4Q

Crystal structure of tubulin in complex with L-DM1-SMe

Summary for 7E4Q

• Entry DOI: 10.2210/pdb7e4q/pdb
• Descriptor: Tubulin alpha-1B chain, (1S,2R,3R,5R,6R,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.1~10,14~.0~3,5~]hexacosa-10(26),11,13,16,18-pentaen-6-yl (2S)-2-{methyl[3-(methyldisulfanyl)propanoyl]amino}propanoate (non-preferred name), PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: microtubule assembly inhibitors, structural protein
• Biological source: Bos taurus (Bovine); More
• Total number of polymer chains: 6
• Total formula weight: 258523.15

Authors

Wang, Y.,Li, W. (deposition date: 2021-02-14, release date: 2021-07-07, Last modification date: 2023-11-29)

Primary citation

Li, W.,Huang, M.,Li, Y.,Xia, A.,Tan, L.,Zhang, Z.,Wang, Y.,Yang, J.
C3 ester side chain plays a pivotal role in the antitumor activity of Maytansinoids.
Biochem.Biophys.Res.Commun., 566:197-203, 2021

PubMed Abstract: Maytansinoids, the chemical derivatives of Maytansine, are commonly used as potent cytotoxic payloads in antibody-drug conjugates (ADC). Structure-activity-relationship studies had identified the C3 ester side chain as a critical element for antitumor activity of maytansinoids. The maytansinoids bearing the methyl group at C3 position with D configuration were about 100 to 400-fold less cytotoxic than their corresponding L-epimers toward various cell lines. The detailed mechanism of how chirality affects the anticancer activity remains elusive. In this study, we determined the high-resolution crystal structure of tubulin in complex with maytansinol, L-DM1-SMe and D-DM1-SMe. And we found the carbonyl oxygen atom of the ester moiety and the tail thiomethyl group at C3 side chain of L-DM1-SMe form strong intramolecular interaction with the hydroxyl at position 9 and the benzene ring, respectively, fixing the bioactive conformation and enhancing the binding affinity. Additionally, ligand-based and structure-based virtually screening methods were used to screen the commercially macrocyclic compounds library, and 15 macrocyclic structures were picketed out as putatively new maytansine-site inhibitors. Our study provides a possible strategy for the rational discovery of next-generation maytansine site inhibitors.

PubMed: 34144258
DOI: 10.1016/j.bbrc.2021.05.071

Experimental method

X-RAY DIFFRACTION (2.501 Å)