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PreprintCited by 15Drug Transport and Resistance MechanismsProtein Structure and DynamicsComputational Drug Discovery Methods

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

Open access
Janaszkiewicz, Angelika, Tóth, Ágota, Faucher, Quentin, Martin, Marving, Chantemargue, Benjamin, Guellec, Chantal Barin-Le, Marquet, Pierre, Di Meo, Florent·2022·Scientific Reports
DOI 10.1101/2022.01.10.475390PMC PMC9054760

Preprint — published as 10.1038/s41598-022-10755-2 · Paper page

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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 h 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 h OAT1 in outward-facing conformation. Taking advantage of the AlphaFold 2 predicted structure of h OAT1 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, h OAT1 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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Metadata

Authors
Janaszkiewicz, A., Tóth, Á., Faucher, Q., Martin, M., Chantemargue, B., Guellec, C. B.-L., Marquet, P., & Di Meo, F.
Affiliations
  • Inserm (FR)
  • Université de Limoges (FR)
ORCID
Venue
Scientific Reports
Publisher
openRxiv
Published
2022-01-12
Volume
12
Issue
1
Pages
7057-7057
ISSN
2045-2322 (ISSN-L)
DOI
10.1101/2022.01.10.475390
PMC
PMC9054760
OpenAlex
W4225246974
Cited by
15
References
1
Citations by year
2026: 3 · 2025: 1 · 2024: 4 · 2023: 7
FWCI
1.25
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • Agence Nationale de la Recherche (ANR‐19, ANR-19-CE17-0020)
  • Institut National de la Santé et de la Recherche Médicale (AAP NA 2019 VICTOR)
  • Grand Équipement National De Calcul Intensif
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
SLC22A6, OAT1, major facilitator superfamily, charge relay system, protein-lipid interactions, phosphatidylethanolamine, membrane protein structure, protein threading, drug transport, xenobiotic removal
MeSH terms
Biological Transport, Humans, Lipid Bilayers, Protein Conformation, Organic Anion Transporters, Organic Anion Transport Protein 1, Molecular Dynamics Simulation

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