9CAX

Structure of human SLC2A9 transporter

Summary for 9CAX

• Entry DOI: 10.2210/pdb9cax/pdb
• EMDB information: 45406
• Descriptor: Soluble cytochrome b562,Solute carrier family 2, facilitated glucose transporter member 9 (1 entity in total)
• Functional Keywords: transporter, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 69859.70

Authors

Khandelwal, N.K.,Gupta, M.,Stroud, R.M. (deposition date: 2024-06-18, release date: 2025-01-29, Last modification date: 2025-08-27)

Primary citation

Khandelwal, N.K.,Gupta, M.,Kumar, P.,Balasubramani, S.G.,Echeverria, I.,Stroud, R.M.
Structural basis of disease mutation and substrate recognition by the human SLC2A9 transporter.
Proc.Natl.Acad.Sci.USA, 122:e2418282122-e2418282122, 2025

PubMed Abstract: 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 Å and 4.1 Å 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.

PubMed: 39937868
DOI: 10.1073/pnas.2418282122

Experimental method

ELECTRON MICROSCOPY (3.37 Å)