Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes

Abstract

The human SLC22A6/OAT1 plays an important role in the disposition of a broad range of endogenous substances and xenobiotics. This is particularly important from the pharmacological point of view since OAT1 is involved in drug elimination events. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despite its significance, the knowledge about OAT1 structure and the transport mechanism at the atomic level remains fragmented owing to the lack of resolved structures. By means of protein-threading modeling refined by μs-scaled Molecular Dynamics simulations, the present study provides the first robust model of hOAT1 in outward-facing conformation. Taking advantage of the AlphaFold 2 predicted structure of hOAT1 in inward-facing conformation, we here provide the essential structural and functional features comparing both states. The intracellular motifs conserved among Major Facilitator Superfamily members create a so-called "charge-relay system" that works as molecular switches modulating the conformation. The principal element of the event points at interactions charged residues that appear crucial for the transporter dynamics and function. Besides, hOAT1 model was embedded in different lipid bilayer membranes highlighting the crucial structural dependence on lipid-protein. MD simulations supported the pivotal role of phosphatidylethanolamine (PE) components on the protein conformation stability. The present model is made available to decipher the impact of any observed polymorphism and mutation on drug transport as well as to understand substrate binding modes.

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

“…3c). However, even though its impact is significant, lipid bilayer contributions appeared milder than in e.g ., Major Facilitator Superfamily membrane transporters 29 .…”

“…As nowadays more attention has been paid to the interplay between the surrounding lipid environment 11,19,22,27,29 and membrane proteins, lipid-dependent protein dynamics and lipid- conformations. On the other hand, our calculations suggest that only EC angle is affected by lipid bilayer composition but only for OF conformations.…”

Substrate binding and lipid-mediated allostery in the human organic anion transporter 1 at the atomic-scale

“…The definition of the co-substrate and substrate required a parametrization using GAFF2 and DNA.OL15 forcefield’s parameters, considering the latter being a purine derivative. MD simulations were performed using a similar setup as previously established [15]. The simulations were carried out with using the CPU and GPU codes of the Amber18 package [40], [41].…”

“…Structural patterns of h OAT1 might provide insights into its roles regarding drug efficacy, toxicity, and elimination [13,14]. We recently proposed a structural and dynamic model of h OAT1 embedded in lipid bilayers [15]. h OAT1 is expected to adopt the Major Facilitator Superfamily (MFS) fold for which substrate translocation follows the alternating access model.…”

“…The so-called A-, E[X 6 ]R and PETL motifs are repeated in both N- and C-bundles. The interactions between these motifs differ between IF and OF conformations [15]. Knowledge about binding modes of h OAT1 substrates remain fragmented while they are of particular importance for the understanding and prediction of transporter-mediated drug-drug interactions (DDIs) [21–23].…”