AI Article Synopsis
- * Inhibitors of hSGLT1 are being explored for potential therapeutic uses, but how they inhibit the transporter is not well understood.
- * The cryo-EM structure of the hSGLT1-MAP17 complex, with the inhibitor LX2761, shows that LX2761 locks the transporter in an open state and blocks water movement, revealing important details about hSGLT1's conformational changes.
Article Abstract
Sodium glucose co-transporters (SGLT) harness the electrochemical gradient of sodium to drive the uphill transport of glucose across the plasma membrane. Human SGLT1 (hSGLT1) plays a key role in sugar uptake from food and its inhibitors show promise in the treatment of several diseases. However, the inhibition mechanism for hSGLT1 remains elusive. Here, we present the cryo-EM structure of the hSGLT1-MAP17 hetero-dimeric complex in the presence of the high-affinity inhibitor LX2761. LX2761 locks the transporter in an outward-open conformation by wedging inside the substrate-binding site and the extracellular vestibule of hSGLT1. LX2761 blocks the putative water permeation pathway of hSGLT1. The structure also uncovers the conformational changes of hSGLT1 during transitions from outward-open to inward-open states.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9616851 | PMC |
| http://dx.doi.org/10.1038/s41467-022-33421-7 | DOI Listing |
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Article Synopsis
- * Inhibitors of hSGLT1 are being explored for potential therapeutic uses, but how they inhibit the transporter is not well understood.
- * The cryo-EM structure of the hSGLT1-MAP17 complex, with the inhibitor LX2761, shows that LX2761 locks the transporter in an open state and blocks water movement, revealing important details about hSGLT1's conformational changes.
Structural Basis of the Selective Sugar Transport in Sodium-Glucose Cotransporters.
J Mol Biol
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Sodium-glucose cotransporters (SGLTs) are responsible for sugar absorption in small intestine and renal tubule epithelial cells. These proteins have attracted clinical attention as a cause of malabsorption and as a target for diabetes drugs. Each SGLT isoform has strict selectivity for its monosaccharide substrate.
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