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U.S.A."],"published-print":{"date-parts":[[2025,2,18]]},"abstract":"<jats:p>Urate provides ~50% of the reducing potential in human and primate plasma which is key to detoxifying reactive oxygen by-products of cellular metabolism. Urate is the endpoint of purine metabolism in primates, and its concentration in plasma is a balance between excretion from kidney and intestine, and subsequent reabsorption in and through cells of kidney proximal tubules to maintain a regulated concentration in plasma. SLC2A9 is the primary transporter that returns urate from the basolateral side of kidney tubule cells back to plasma. A shorter splice variant of SLC2A9 is directed to the apical surface where several transporters recapture urate from the tubule back into cells. Too high a concentration in plasma causes hyperuricemia, is linked to gout, and favors kidney stone formation. To understand the molecular basis of uric acid transport and the role of disease-causing mutations in SLC2A9, we determined structures of human SLC2A9 in its apo form, and its urate-bound form by cryo-EM, at resolution of 3.3 \u00c5 and 4.1 \u00c5 respectively. Both structures are captured in an inward open conformation. Using the inward-facing structure as a template we modeled the outward-facing conformation to understand the alternating access mechanism. Alternative salt bridge pairs on the cytoplasmic side suggest a mechanism that can balance the energetics of the inward open and outward open states. The location of disease-causing mutants suggests their role in impacting function. Our structures elucidate the molecular basis for urate selectivity and transport and provide a platform for future structure-based drug discovery aimed at reducing plasma urate levels in diseases of hyperuricemia and gout.<\/jats:p>","DOI":"10.1073\/pnas.2418282122","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T13:47:01Z","timestamp":1739368021000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Structural basis of disease mutation and substrate recognition by the human SLC2A9 transporter"],"prefix":"10.1073","volume":"122","author":[{"given":"Nitesh Kumar","family":"Khandelwal","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of California, San Francisco","place":["San 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