Li Hongwu, Gong Weikang
School of Mathematics and Statistics, Nanyang Normal University, Nanyang, China.
Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, China.
Front Med (Lausanne). 2022 Feb 9;9:815355. doi: 10.3389/fmed.2022.815355. eCollection 2022.
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 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.
人P-糖蛋白（P-gp）是一种ATP结合盒（ABC）转运蛋白。一旦人P-gp在肿瘤细胞中过表达，就会导致肿瘤多药耐药（MDR）。然而，目前的实验方法难以获得人P-gp大规模的构象转变过程。在这项工作中，我们用两态各向异性网络模型（tANM）探索了人P-gp在底物转运过程中从内向（IF）状态到外向（OF）状态的变构途径。这些结果表明变构转变以耦合方式进行。核苷酸结合结构域（NBDs）的构象变化最终使跨膜结构域（TMDs）转变为OF状态——细胞内螺旋IH1和IH2的变构传播作用。此外，与其他方法相比，这种变构途径在能量方面具有优势。这项研究揭示了P-gp的构象转变，有助于理解ABC转运蛋白的变构机制。
