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Structure of hSGLT2-MAP17 complex in the substrate-free inward-facing conformation in the presence of sodium
Structural highlights
DiseaseSC5A2_HUMAN Familial renal glucosuria. The disease is caused by variants affecting the gene represented in this entry. FunctionSC5A2_HUMAN Electrogenic Na(+)-coupled sugar symporter that actively transports D-glucose at the plasma membrane, with a Na(+) to sugar coupling ratio of 1:1. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump (PubMed:20980548, PubMed:28592437, PubMed:34880493). Has a primary role in D-glucose reabsorption from glomerular filtrate across the brush border of the early proximal tubules of the kidney (By similarity).[UniProtKB:Q923I7][1] [2] [3] Publication Abstract from PubMedGlucose is a vital energy source essential for life and human health. Sodium-glucose cotransporter 2 (SGLT2) is a sodium-glucose symporter that utilizes the electrochemical gradient of sodium to reabsorb glucose from kidney filtrate back into circulation. SGLT2 plays a crucial role in maintaining blood glucose homeostasis and is an important drug target for type 2 diabetes. Despite its significance, the mechanisms by which SGLT2 recognizes and releases substrates during its transport cycle remain largely unknown. Here, we present structures of human SGLT2 in complex with a glucose analogue in the occluded conformation at 2.6 A resolution, revealing a detailed hydrogen bonding network at the substrate binding site that governs substrate recognition. Additionally, structures of SGLT2 in both the substrate-bound inward-facing conformation and the substrate-free inward-facing conformations illustrate the structural changes that occur during substrate release into cytosol. Our structural analysis, combined with mutagenesis results, identifies specific polar interactions that are essential for maintaining the outer and inner gates in their closed conformations. Mechanism of substrate recognition and release of human SGLT2.,Cui W, Sun Z, Xu J, Liu X, Kang Y, Chen L Nat Commun. 2025 Aug 4;16(1):7140. doi: 10.1038/s41467-025-62421-6. PMID:40759649[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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