7WMV

Structure of human SGLT1-MAP17 complex bound with LX2761

Summary for 7WMV

• Entry DOI: 10.2210/pdb7wmv/pdb
• EMDB information: 32617
• Descriptor: Sodium/glucose cotransporter 1, PDZK1-interacting protein 1, N-[2-(dimethylamino)ethyl]-2-methyl-2-[4-[4-[[2-methyl-5-[(2S,3R,4R,5S,6R)-6-methylsulfanyl-3,4,5-tris(oxidanyl)oxan-2-yl]phenyl]methyl]phenyl]butanoylamino]propanamide (3 entities in total)
• Functional Keywords: glucose transporter, sglt, sodium glucose transporter, membrane protein, protein transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 86424.59

Authors

Chen, L.,Niu, Y.,Cui, W. (deposition date: 2022-01-17, release date: 2022-11-16, Last modification date: 2024-11-06)

Primary citation

Niu, Y.,Cui, W.,Liu, R.,Wang, S.,Ke, H.,Lei, X.,Chen, L.
Structural mechanism of SGLT1 inhibitors.
Nat Commun, 13:6440-6440, 2022

PubMed 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.

PubMed: 36307403
DOI: 10.1038/s41467-022-33421-7

Experimental method

ELECTRON MICROSCOPY (3.2 Å)