On the interplay between lipids and asymmetric dynamics of an NBS degenerate ABC transporter

Abstract

Multidrug resistance-associated proteins are ABC C-family exporters. They are crucial in pharmacology as they transport various substrates across membranes. However, the role of the degenerate nucleotide-binding site (NBS) remains unclear likewise the interplay with the surrounding lipid environment. Here, we propose a dynamic and structural overview of MRP1 from ca. 110 μs molecular dynamics simulations. ATP binding to NBS1 is likely maintained along several transport cycles. Asymmetric NBD behaviour is ensured by lower signal transduction from NBD1 to the rest of the protein owing to the absence of ball-and-socket conformation between NBD1 and coupling helices. Even though surrounding lipids play an active role in the allosteric communication between the substrate-binding pocket and NBDs, our results suggest that lipid composition has a limited impact, mostly by affecting transport kinetics. We believe that our work can be extended to other degenerate NBS ABC proteins and provide hints for deciphering mechanistic differences among ABC transporters.

Computational and structural insights into the pre- and post-hydrolysis states of bovine multidrug resistance associated protein 1 (MRP1)

“…This is in agreement with the recent structural findings suggesting that ABC transporter might adopt UR state prior to get back to IF conformational state, resetting the transport cycle 17 . However, the use of NBD distances should be carefully considered, especially, for NBD degenerate ABC transporters such as MRP1, given the expected pivotal role of ATP-bound NBS1 in maintaining NBD dimerization along the transport cycle 15 , in agreement with our previous findings 14 .…”

“…MD simulations performed for the pre-hydrolysis state, namely OF b MRP1-(ATP) 2 were taken from our previous work 14 . In the present study, the post-hydrolysis state (namely OF b MRP1-ATP-ADP) was built adopting the exact same protocol 14 .…”

“…Allostery network pathways, as previously 14 , were determined using the Allopath approach developed by Westerlund et al 52,53 . Distant "communication efficiency" between two domains was obtained from the contact map and the mutual information matrix of protein residues and non-protein interactors such as surrounding lipid and bound nucleotides.…”

“…Namely, the structures of IF apo (PDB ID: 5UJ9 6 ), IF substrate-bound (PDB ID: 5UJA 6 ) as well as both the pre- and post-hydrolysis states under OF conformation (PDB IDs: 6BHU 7 and 6UY0 12 , respectively) were resolved, providing an overview of large-scale transitions occurring along the transport cycle. We recently investigated b MRP1 conformations in various lipid bilayer models by molecular dynamics (MD) simulations, suggesting that the NBD asymmetry is key in ATP and substrate-binding events as well as in the allosteric communication between nucleotide binding sites (NBSs) and substrate-binding pocket 14 . Furthermore, the interplay between b MRP1 and lipid bilayer models was also investigated, suggesting an active role of the surrounding lipids in the IF-to-OF transition of b MRP1, and highlighting direct interactions between phosphatidylethanolamine lipids and cholesterol molecules.…”

“…Furthermore, the interplay between b MRP1 and lipid bilayer models was also investigated, suggesting an active role of the surrounding lipids in the IF-to-OF transition of b MRP1, and highlighting direct interactions between phosphatidylethanolamine lipids and cholesterol molecules. Such lipids were shown to actively participate in the distance communications between NBSs and the substrate-binding pocket 10,14 . However, focus was mostly paid to the dynamics of milestone conformations along the IF-to-OF transition, prior to ATP-hydrolysis.…”