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bioRxiv · 10.1101/2022.01.10.475390

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

Janaszkiewicz, A.·Toth, A.·Faucher, Q.·Martin, M.·Chantemargue, B.·Barin-Le Guellec, C.·Marquet, P.·Di Meo, F.
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Abstract

The human SLC22A6/OAT1 plays an important role in the elimination of a broad range of endogenous substances and xenobiotics thus attracting attention from the pharmacological community. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despite its significance, the knowledge about hOAT1 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 s-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 of charged residues that appear crucial for the transporter dynamics and function. Moreover, hOAT1 model was embedded in different lipid bilayer membranes highlighting the crucial structural dependence on lipid-protein interactions. MD simulations supported the pivotal role of phosphatidylethanolamine components to 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.

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Janaszkiewicz, A., Toth, A., Faucher, Q., Martin, M., Chantemargue, B., Barin-Le Guellec, C., Marquet, P., Di Meo, F.. 2022-01-12. Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes. https://doi.org/10.1101/2022.01.10.475390

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