Structural basis of inhibition of the human SGLT2-MAP17 glucose transporter.
Nature
; 601(7892): 280-284, 2022 01.
Article
em En
| MEDLINE
| ID: mdl-34880493
ABSTRACT
Human sodium-glucose cotransporter 2 (hSGLT2) mediates the reabsorption of the majority of filtrated glucose in the kidney1. Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes1. Here we determined the cryogenic electron microscopy structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state to an overall resolution of 2.95 Å. Our structure shows eukaryotic SGLT-specific structural features. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle. Our work provides a framework for understanding the mechanism of SLC5A family glucose transporters and also develops a foundation for the future rational design and optimization of new inhibitors targeting these transporters.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transportador 2 de Glucose-Sódio
/
Inibidores do Transportador 2 de Sódio-Glicose
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article