ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodiscreconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the "access tunnel." This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors.
|Original language||English (US)|
|Number of pages||9|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Oct 20 2020|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank Miroslav Peterek of the Scientific Center for Optical and Electron Microscopy (ScopeM) at ETH Zürich for technical support. We also acknowledge Nina Tremp for help with antibody expression and purification. This research was supported by grants from the Swiss Cancer League (to K.P.L.), the Swiss National Science Foundation (SNF) through National Centers of Competence in Research Structural Biology and TransCure, as well as SNF grant 310030_189111 to K.P.L. Further support was provided by the Japan Society for the Promotion of Science, Ministry of Education, Culture, Sports, Science and Technology (SPS-MEXT, grant JP17H06327 to N.F.).
© 2020 National Academy of Sciences. All rights reserved.
- ABC transporter
- Single-particle cryoelectron microscopy