9CBB

Structure of urate bound human SLC2A9 transporter

9CBB の概要

• エントリーDOI: 10.2210/pdb9cbb/pdb
• EMDBエントリー: 45421
• 分子名称: Soluble cytochrome b562,Solute carrier family 2, facilitated glucose transporter member 9, URIC ACID (2 entities in total)
• 機能のキーワード: transporter, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 70027.81

構造登録者

Khandelwal, N.K.,Gupta, M.,Stroud, R.M. (登録日: 2024-06-18, 公開日: 2025-01-29, 最終更新日: 2025-08-27)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (4.15 Å)