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

The Organic Anion Transporter 1 is a membrane transporter known for its central role in drug elimination by the kidney. hOAT1 is an antiporter translocating substrate in exchange for a-ketoglutarate. The understanding of hOAT1 structure and function remains limited due to the absence of resolved structure of hOAT1. Benefiting from conserved structural and functional patterns shared with other Major Facilitator Superfamily transporters, the present study intended to investigate fragments of hOAT1 transport function and modulation of its activity in order to make a step forward the understanding of its transport cycle. mu s-long molecular dynamics simulation of hOAT1 were carried out suggesting two plausible binding sites for a typical substrate, adefovir, in line with experimental observations. The well-known B-like motif binding site was observed in line with previous studies. However, we here propose a new inner binding cavity which is expected to be involved in substrate translocation event. Binding modes of hOAT1 co-substrate alpha-ketoglutarate were also investigated suggesting that it may bind to highly conserved intracellular motifs. We here hypothesise that alpha-ketoglutarate may disrupt the pseudosymmetrical intracellular charge-relay system which in turn may participate to the destabilisation of OF conformation. Investigations regarding allosteric communications along hOAT1 also suggest that substrate binding event might modulate the dynamics of intracellular charge relay system, assisted by surrounding lipids as active partners. We here proposed a structural rationalisation of transport impairments observed for two single nucleotide polymorphisms, p.Arg50His and p.Arg454Gln suggesting that the present model may be used to transport dysfunctions arising from hOAT1 mutations.

Automated summary

The Organic Anion Transporter 1 (hOAT1) is a membrane transporter involved in drug elimination by the kidney. This study aimed to investigate fragments of hOAT1 structure and function in order to better understand its transport cycle. Molecular dynamics simulations suggested two potential binding sites for the substrate adefovir, including a new inner binding cavity. The binding modes of the co-substrate alpha-ketoglutarate were also explored. The findings provide insights into the transport impairments caused by hOAT1 mutations.