8HDH

Structure of human SGLT2-MAP17 complex with Canagliflozin

Summary for 8HDH

• Entry DOI: 10.2210/pdb8hdh/pdb
• EMDB information: 34673
• Descriptor: Sodium/glucose cotransporter 2, PDZK1-interacting protein 1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: ion transport, sodium transport, sugar transport, symport, transport, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 86171.42

Authors

Hiraizumi, M.,Kishida, H.,Miyaguchi, I.,Nureki, O. (deposition date: 2022-11-04, release date: 2023-11-08, Last modification date: 2024-10-23)

Primary citation

Hiraizumi, M.,Akashi, T.,Murasaki, K.,Kishida, H.,Kumanomidou, T.,Torimoto, N.,Nureki, O.,Miyaguchi, I.
Transport and inhibition mechanism of the human SGLT2-MAP17 glucose transporter.
Nat.Struct.Mol.Biol., 31:159-169, 2024

PubMed Abstract: 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.

PubMed: 38057552
DOI: 10.1038/s41594-023-01134-0

Experimental method

ELECTRON MICROSCOPY (3.1 Å)