8hdh | pdb_00008hdh

Structure of human SGLT2-MAP17 complex with Canagliflozin

spinqualitylabelsall models 8hdh, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8hdh is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.1Å Ligands: L3R, NA, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SC5A2_HUMAN Familial renal glucosuria. The disease is caused by variants affecting the gene represented in this entry. Function SC5A2_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] Publication Abstract from PubMed Sodium-glucose cotransporter 2 (SGLT2) is imporant in glucose reabsorption. SGLT2 inhibitors suppress renal glucose reabsorption, therefore reducing blood glucose levels in patients with type 2 diabetes. We and others have developed several SGLT2 inhibitors starting from phlorizin, a natural product. Using cryo-electron microscopy, we present the structures of human (h)SGLT2-MAP17 complexed with five natural or synthetic inhibitors. The four synthetic inhibitors (including canagliflozin) bind the transporter in the outward conformations, while phlorizin binds it in the inward conformation. The phlorizin-hSGLT2 interaction exhibits biphasic kinetics, suggesting that phlorizin alternately binds to the extracellular and intracellular sides. The Na(+)-bound outward-facing and unbound inward-open structures of hSGLT2-MAP17 suggest that the MAP17-associated bundle domain functions as a scaffold, with the hash domain rotating around the Na(+)-binding site. Thus, Na(+) binding stabilizes the outward-facing conformation, and its release promotes state transition to inward-open conformation, exhibiting a role of Na(+) in symport mechanism. These results provide structural evidence for the Na(+)-coupled alternating-access mechanism proposed for the transporter family. Transport and inhibition mechanism of the human SGLT2-MAP17 glucose transporter.,Hiraizumi M, Akashi T, Murasaki K, Kishida H, Kumanomidou T, Torimoto N, Nureki O, Miyaguchi I Nat Struct Mol Biol. 2024 Jan;31(1):159-169. doi: 10.1038/s41594-023-01134-0. , Epub 2023 Dec 6. PMID:38057552 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Sodium/glucose cotransporter 3D structures

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