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

2022 ◽  
Author(s):  
Angelika Janaszkiewicz ◽  
Ágota Tóth ◽  
Quentin Faucher ◽  
Marving Martin ◽  
Benjamin Chantemargue ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Organic Anion ◽  
Major Facilitator Superfamily ◽  
Organic Anion Transporter ◽  
Lipid Bilayer Membranes ◽  
Bilayer Membranes ◽  
Anion Transporter ◽  
Functional Features ◽  
And Function ◽  
The Impact

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.

scholarly journals MODELING OF GLYCEROL-3-PHOSPHATE TRANSPORTER SUGGESTS A POTENTIAL 'TILT' MECHANISM INVOLVED IN ITS FUNCTION

2008 ◽  
Vol 06 (05) ◽  
pp. 885-904 ◽  
Author(s):  
IGOR F. TSIGELNY ◽  
JERRY GREENBERG ◽  
VALENTINA KOUZNETSOVA ◽  
SANJAY K. NIGAM
Keyword(s):  
Molecular Dynamics ◽  
Organic Anion ◽  
Steered Molecular Dynamics ◽  
Major Facilitator Superfamily ◽  
Organic Anion Transporter ◽  
Phosphate Transporter ◽  
Anion Transporter ◽  
Transporter Family ◽  
Mfs Transporters ◽  
The Impact

Many major facilitator superfamily (MFS) transporters have similar 12-transmembrane α-helical topologies with two six-helix halves connected by a long loop. In humans, these transporters participate in key physiological processes and are also, as in the case of members of the organic anion transporter (OAT) family, of pharmaceutical interest. Recently, crystal structures of two bacterial representatives of the MFS family — the glycerol-3-phosphate transporter (GlpT) and lac-permease (LacY) — have been solved and, because of assumptions regarding the high structural conservation of this family, there is hope that the results can be applied to mammalian transporters as well. Based on crystallography, it has been suggested that a major conformational "switching" mechanism accounts for ligand transport by MFS proteins. This conformational switch would then allow periodic changes in the overall transporter configuration, resulting in its cyclic opening to the periplasm or cytoplasm. Following this lead, we have modeled a possible "switch" mechanism in GlpT, using the concept of rotation of protein domains as in the DynDom program17and membranephilic constraints predicted by the MAPAS program.23We found that the minima of energies of intersubunit interactions support two alternate positions consistent with their transport properties. Thus, for GlpT, a "tilt" of 9°–10° rotation had the most favorable energetics of electrostatic interaction between the two halves of the transporter; moreover, this confirmation was sufficient to suggest transport of the ligand across the membrane. We conducted steered molecular dynamics simulations of the GlpT-ligand system to explore how glycerol-3-phosphate would be handled by the "tilted" structure, and obtained results generally consistent with experimental mutagenesis data. While biochemical data remain most consistent with a single-site alternating access model, our results raise the possibility that, while the "rocker switch" may apply to certain MFS transporters, intermediate "tilted" states may exist under certain circumstances or as transitional structures. Although wet lab experimental confirmation is required, our results suggest that transport mechanisms in this transporter family should probably not be assumed to be conserved simply based on standard structural homology considerations. Furthermore, steered molecular dynamics elucidating energetic interactions of ligands with amino acid residues in an appropriately modeled transporter may have predictive value in understanding the impact of mutations and/or polymorphisms on transporter function.

scholarly journals Pharmacokinetic Changes during Pregnancy According to Genetic Variants: a Prospective Study in HIV-Infected Patients Receiving Atazanavir-Ritonavir

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Emanuele Focà ◽  
Andrea Calcagno ◽  
Andrea Bonito ◽  
Jessica Cusato ◽  
Elisabetta Domenighini ◽  
...  
Keyword(s):  
Prospective Study ◽  
Genetic Variants ◽  
Organic Anion ◽  
Pregnane X Receptor ◽  
Organic Anion Transporter ◽  
Nucleotide Polymorphisms ◽  
Third Trimester ◽  
Anion Transporter ◽  
A Prospective Study ◽  
The Impact

ABSTRACT Atazanavir-ritonavir concentrations change over time during pregnancy in HIV-positive patients; the impact of genetic variants is unknown. Twenty patients were enrolled in this study; plasma and intracellular concentrations of antiretrovirals were measured, in addition to single-nucleotide polymorphisms in transport-related genes. Linear logistic regression showed that genetic variants in organic-anion-transporter-1B1- and pregnane-X-receptor-encoding genes affected third-trimester atazanavir exposure. In this prospective study, genetic variants partially explained the observed interpatient variability in third-trimester exposure to antiretrovirals.

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