Molecular mechanisms of uric acid transport by the native human URAT1 and its inhibition by anti-gout drugs

Wu, C.; Zhang, C.; Jin, S.; Wang, J. J.; Dai, A.; Xu, J.; Zhang, H.; Yang, X.; He, X.; Yuan, Q.; Hu, W.; Xu, Y.; Wang, M.-W.; Jiang, Y.; Yang, D.; Xu, H. E.

doi:10.1101/2024.09.11.612394

bioRxiv · 10.1101/2024.09.11.612394

Molecular mechanisms of uric acid transport by the native human URAT1 and its inhibition by anti-gout drugs

Wu, C.·Zhang, C.·Jin, S.·Wang, J. J.·Dai, A.·Xu, J.·Zhang, H.·Yang, X.·He, X.·Yuan, Q.·Hu, W.·Xu, Y.·Wang, M.-W.·Jiang, Y.·Yang, D.·Xu, H. E.

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Abstract

Gout, a common and painful disease, stems from hyperuricemia, where elevated blood uric acid levels lead to urate crystal formation in joints and kidneys. The human urate transporter 1 (hURAT1) plays a critical role in urate homeostasis by facilitating urate reabsorption in the renal proximal tubule, making it a key target for gout therapy. Pharmacological inhibition of hURAT1 with drugs such as dotinurad, benzbromarone, lesinurad, and verinurad promotes uric acid excretion and alleviates gout symptoms. Here we present cryo-electron microscopy structures of native hURAT1 bound with these anti-gout drugs in the inward-open state, and with uric acid in inward-open, outward-open, and occluded states. Complemented by mutagenesis and cell-based assays, these structures reveal the mechanisms of uric acid reabsorption and hURAT1 inhibition. Our findings elucidate the molecular basis of uric acid transport and anti-gout medication action, and provide a structural framework for the rational design of next-generation therapies for hyperuricemia and gout.

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Wu, C., Zhang, C., Jin, S., Wang, J. J., Dai, A., Xu, J., Zhang, H., Yang, X., He, X., Yuan, Q., Hu, W., Xu, Y., Wang, M.-W., Jiang, Y., Yang, D., Xu, H. E.. 2024-09-11. Molecular mechanisms of uric acid transport by the native human URAT1 and its inhibition by anti-gout drugs. https://doi.org/10.1101/2024.09.11.612394

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