AUTHOR=Li Hongwu , Gong Weikang TITLE=Study of Allosteric Transitions of Human P-Glycoprotein by Using the Two-State Anisotropic Network Model JOURNAL=Frontiers in Medicine VOLUME=9 YEAR=2022 URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.815355 DOI=10.3389/fmed.2022.815355 ISSN=2296-858X ABSTRACT=

Human P-glycoprotein (P-gp) is a kind of ATP-binding cassette (ABC) transporters. Once human P-gp is overexpressed in tumor cells, which can lead to tumor multidrug resistance (MDR). However, the present experimental methods are difficult to obtain the large-scale conformational transition process of human P-gp. In this work, we explored the allosteric pathway of human P-gp from the inward-facing (IF) to the outward-facing (OF) state in the substrate transport process with the two-state anisotropic network model (tANM). These results suggest that the allosteric transitions proceed in a coupled way. The conformational changes of nucleotide-binding domains (NBDs) finally make the transmembrane domains (TMDs) to the OF state via the role of the allosteric propagation of the intracellular helices IH1 and IH2. Additionally, this allosteric pathway is advantageous in energy compared with other methods. This study reveals the conformational transition of P-gp, which contributes to an understanding of the allosteric mechanism of ABC exporters.