Insight into URAT1’s Role in Gout Therapeutics
Researchers from St. Jude Children’s Research Hospital have successfully created ten different structures of URAT1, a protein associated with gout. Gout results from high levels of urate, which is produced during the breakdown of purines—molecules crucial for DNA and RNA production. URAT1 serves as a transporter that manages urate levels by regulating its reabsorption in the kidneys. Although URAT1 is a target for gout medications, its mechanics and the impact of mutations or drugs on it were not well understood. The new structures shed light on how URAT1 facilitates urate transport and pave the way for future drug development. These findings were published today in Cell Research.
The kidneys play a key role in maintaining the balance between metabolite creation and elimination. Any imbalance, whether resulting in too much or too little removal of metabolites, can affect the body’s overall health. Urate (or uric acid) accumulates when the body breaks down purines. Excess urate can crystallize in joints, leading to gout. The URAT1 transporter helps manage urate levels by allowing its reabsorption while expelling chloride ions from kidney cells.
A Comprehensive Perspective on Urate Transport
Despite the crucial link between URAT1 and conditions like gout, knowledge about its functionality was limited. While gout therapies exist, their mechanisms were also unclear. Chia-Hsueh Lee, PhD, from the Department of Structural Biology, aimed to bridge this information gap. “We wanted to uncover the structural mechanism of this transporter to ultimately create improved drugs for gout,” Lee stated.
URAT1 belongs to the SLC22 family of transporters. Although structural data exists for other members, they typically show the protein in an inward-facing position. “To truly understand how a transporter operates, having multiple conformations is beneficial,” explained Yaxin Dai, PhD, also from Structural Biology. “In our research, we captured three distinct shapes: inward-facing, outward-facing, and an occluded state that prevents access from both sides of the cell.”
The team discovered that URAT1 operates differently than other transporters in the SLC22 family. “The amino acid sequence of URAT1 suggests it has adapted to transport different substances, but structural data was essential to identify which amino acids were crucial,” said Lee. “Thanks to these structures, we can now pinpoint the exact amino acids that interact with the substrate, differentiating them from other SLC22 transporters.”
Linking Structures to Drug Action and Disease Mechanisms
The researchers followed up by analyzing URAT1 structures in the presence of three gout medications: lesinurad, verinurad, and dotinurad. “The inhibitors are clearly visible, showing that in all three scenarios, URAT1 remains in the inward-facing position. This indicates that these drugs effectively stabilize the protein in this form,” Dai noted. “We conclude that the drugs work by preventing URAT1 from changing to an outward-facing position.”
In addition to providing insights into how the protein functions and how gout medications exert their effects, these structures also enable scientists to study URAT1 mutations associated with hypouricemia and other kidney-related disorders. “Understanding how specific mutations impact the transporter was challenging without structural data. Now we can correlate these genetic variations with the structure and clarify their impacts,” Lee mentioned. “This represents significant progress toward comprehending diseases associated with URAT1.”
This research was supported by grants from the National Institutes of Health (R01GM143282 and R01NS133147) and ALSAC, St. Jude’s fundraising and awareness organization.
