Mechanism of high affinity inhibition of the human urate transporter URAT1.

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Tan PK, Ostertag TM, Miner JN

Mechanism of high affinity inhibition of the human urate transporter URAT1.

Sci Rep. 2016 Oct 7;6:34995. doi: 10.1038/srep34995.

PubMed ID

27713539 [ View in PubMed

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Abstract

Gout is caused by elevated serum urate levels, which can be treated using inhibitors of the uric acid transporter, URAT1. We exploited affinity differences between the human and rat transporters to map inhibitor binding sites in URAT1. Human-rat transporter chimeras revealed that human URAT1 serine-35, phenylalanine-365 and isoleucine-481 are necessary and sufficient to provide up to a 100-fold increase in affinity for inhibitors. Moreover, serine-35 and phenylalanine-365 are important for high-affinity interaction with the substrate urate. A novel URAT1 binding assay provides support for direct interaction with these amino acids; thus, current clinically important URAT1 inhibitors likely bind the same site in URAT1. A structural model suggests that these three URAT1 residues are in close proximity potentially projecting within the channel. Our results indicate that amino acids from several transmembrane segments functionally cooperate to form a high-affinity URAT1 inhibitor binding site that, when occupied, prevents substrate interactions.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sulfinpyrazone	Solute carrier family 22 member 12	Protein	Humans	Yes	Inhibitor	Details