A team led by professor Yang Jinliang, from State/National Key Laboratory of Biotherapy (SKLB), West China Hospital, Sichuan University, published a paper titled “Mechanism of Microtubule Stabilization by Taccalonolide AJ” (link to this paper: http://www.nature.com/articles/ncomms15787
) in the prestigious international journal Nature Communications. Financial support for this work was provided by National Major Scientific and Technological Special Project for “Significant New Drugs Development” (2012ZX09103301-030), and National Natural Science Foundation of China (81372822, 81501368 and 81672722).
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 the team of Yang Jinliang 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, they propose that the β-tubulin E-site is locked into a GTP-preferred status by AJ binding. Their results provide experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance.
Chen Qiang, associate researcher as well as co-corresponding author of this paper, has participated in later-stage data analysis and relevant experiment. Dr. Benoît Gigant, professor of French Academy of Sciences (Cell 2000,102, 809-816; Nature 2004,428, 198-202; Nature 2005, 435, 519-522; Nature structural & molecular biology 2013, 20, 1001-1007.) as well as co-corresponding author of this paper, has provided certain guidance and assistance to this research. Besides, it’s worth mentioning that Dr. Wang Yuxi, first author of this paper, has already explained the interaction between Microtubule-stabilizing agents (MSAs) and tubulin based on the technology of structural biology, and published 3 influential SCI papers in 2016, either as co-lead author or lead author. West China Hospital, Sichuan University has also been lead author as well as the affiliation of lead author.
An introduction to the authors of the paper:
Yang Jinliang, professor in Statel Key Laboratory of Biotherapy (SKLB), West China Hospital, Sichuan University, and director in Genetic Engineering Antibody Lab, majors in Cellular Biology of Tumor, Antibody Drug Development, as well as Gene Immunotherapy for Cancer and Proteomics. Recently, he has published more than 60 papers as a corresponding author in several core journals, such as Nature Communications, Angew. Chem. Int. Ed., J Control Release, Molecular Pharmacology, Journal of Molecular Medicine, as well as FEBS Journal, and obtained 6 patents.
Chen Qiang, associate researcher, mainly studies the relation between biological macromolecule’s structure and the function through X-Ray Crystallography and other experimental methods. He has hitherto published 21 SCI papers in influential journals, such as Nature, Nature Communications, Science Advances, PNAS, JCS, FASEB J, JMB, and FEBS J. Two of his papers are recommended by “Faculty of 1000,” and he himself is invited to review papers for Cell Research, BMC Genomics, and Scientific Reports.