Scientists at St. Jude Children’s Research Hospital have used cryo-electron microscopy to generate structures of URAT1, a protein linked to gout. URAT1 is a transporter that regulates urate levels in the kidneys, controlling its reabsorption. Little was known about how URAT1 works or how mutations or drugs affect its activity. The new structures of URAT1, combined with substrates and inhibitors, shed light on the mechanism by which URAT1 transports urate, providing insights for future drug discovery efforts. The findings were published in Cell Research.
The balance of metabolite production and removal is crucial, with the kidneys playing a key role in this process. Urate is a byproduct of purine metabolism, vital for DNA and RNA synthesis. When urate levels increase, it can lead to the formation of crystals in the joints, causing gout. URAT1 helps regulate urate reabsorption by moving chloride ions out of kidney cells, acting like a doorman at a club. Understanding its function is essential for treating gout and maintaining metabolic homeostasis.
Despite the importance of URAT1 in diseases like gout and its role in metabolic regulation, little was known about its mechanism of action. Researchers at St. Jude sought to fill this knowledge gap to develop better treatments for gout. By studying the structures of URAT1, they discovered different conformations, including inward-facing, outward-facing, and occluded states. These findings revealed how URAT1 functions differently from other SLC22 family members, providing insight into the transporter’s substrate specificity.
The researchers obtained structures of URAT1 in the presence of three gout therapeutics: lesinurad, verinurad, and dotinurad. They found that the inhibitors effectively kept URAT1 in the inward-facing state, indicating how these drugs work to treat gout by locking the protein in a specific conformation. The structures also allowed the researchers to explore the rationale behind URAT1 mutations linked to hypouricemia and other kidney diseases. Mapping genetic variations onto the structure helps explain how specific mutations affect transporter function.
The study was supported by grants from the National Institutes of Health and ALSAC, the fundraising organization of St. Jude. The findings provide a deeper understanding of URAT1’s transport mechanism, drug interactions, and disease implications. By elucidating the structural basis of URAT1 function, researchers hope to pave the way for more effective treatments for gout and other diseases linked to urate transport dysregulation. This study represents a significant step forward in understanding the molecular mechanisms underlying gout and related metabolic disorders.