Current Updates in the Genetic Polymorphisms of Human Organic Anion Transporters (OATs)

Li, Zhen; Lam, Ping Hei; Zhu, Ling; Wang, Ke; Zhou, Fanfan

doi:10.4172/2153-0645.1000e127

Cited by 2 publications

(2 citation statements)

References 59 publications

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“…Beyond pharmacologically relevant mechanistic insights into hOAT1-mediated drug transport, the present structural model can also be used to understand the modulation of substrate transport across cell membranes by naturally-occurring polymorphisms in genes coding transporters [60][61][62][63]. Several SNPs in hOAT1 were identified and classified according to ethnical origins and species [35].…”

Section: Structural Mapping Of Hoat1 Single Nucleotide Polymorphisms ...mentioning

confidence: 99%

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

Janaszkiewicz¹,

Tóth²,

Faucher³

et al. 2023

Biomedicine & Pharmacotherapy

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Section: Structural Mapping Of Hoat1 Single Nucleotide Polymorphisms ...mentioning

confidence: 99%

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

Janaszkiewicz¹,

Tóth²,

Faucher³

et al. 2023

Biomedicine & Pharmacotherapy

View full text Add to dashboard Cite

“…Beyond pharmacologically relevant mechanistic insights into hOAT1-mediated drug transport, the present structural model substrate can also be used to understand the modulation of substrate transport across cell membranes by naturally-occurring polymorphisms in genes coding transporters [59][60][61][62]. Several SNPs in hOAT1 were identified and classified according to ethnical origins and species [34].…”

Section: Structural Mapping Of Hoat1 Single Nucleotide Polymorphismsmentioning

confidence: 99%

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

Janaszkiewicz

Tóth

Faucher

et al. 2022

Preprint

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The Organic Anion Transporter 1 is a membrane transporter known for its central role in drug elimination by the kidney. hOAT1 is an antiporter, i.e., it translocates substrate in exchange for a-ketoglutarate. The pharmacological attention is drawn by hOAT1-mediated drug-drug interactions which may lead to adverse effects. Nonetheless, the understanding of hOAT1 structure and function remains limited due to the absence of resolved structure of hOAT1. However, owing to conserved structural and functional patterns shared within Major Facilitator Superfamily (MFS) that OAT1 belongs to, an opportunity appeared for structure modelling by protein structure prediction tools and molecular dynamics simulations. Taking advantage of formerly validated hOAT1 models, the present work investigated substrate and co-substrate binding to hOAT1, paying attention to allostery between key hOAT1 domains. Dynamic pictures were provided by microsecond-scaled molecular dynamic simulations of hOAT1 OF bounded to adefovir and/or a-ketoglutarate embedded into POPC-based membranes. Our computational approach has revealed key residues of two binding pockets for adefovir. a-Ketoglutarate might bind to the intracellular charge-relay system highly conserved motifs within MFS. Allostery between these binding pockets was also investigated highlighting the active role of the surrounding lipid bilayer. Lastly, using the structure of hOAT1 in OF as well as inward-facing conformation obtained from AlphaFold 2 (AF2) structure prediction tool, we proposed a structural rationalization of transport impairments experimentally observed for 2 significant single nucleotide polymorphisms, namely Arg50His and Arg454Gln.

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Current Updates in the Genetic Polymorphisms of Human Organic Anion Transporters (OATs)

Cited by 2 publications

References 59 publications

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

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

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

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