Cryo-EM structures of ABCC1 revealing new conformational dynamics in the resting state

ABCC1/MRP1 in the C branch of Adenosine triphosphate binding cassette (ABC) transporters superfamily, is directly linked to multiple drug resistance in chemotherapy. Here, to further understand the conformational dynamics of ABCC1, we performed single-particle cryo-electron microscopy analysis of purified bovine ABCC1. Two conformational states were found coexisted with nearly equal population. While one state has a wider substrate transporting pathway, akin to the previously reported apo structure, the other is narrower, despite the empty substrate pocket. In addition, multiple lipid-binding interfaces were identified based on the presence of rod-shaped, unmodeled, non-protein densities in the resolved density maps, potentially contributing to the stabilization of TMD0 domain and activity regulation of ABCC1. Further, we found that three asparagine residues in bovine ABCC1 are glycosylated. Together, our study provides fresh insights into the structural features and conformational dynamics of bovine ABCC1, offering a new framework for understanding the function and regulatory mechanisms of ABCC1.