SGLT2

February 2023

Sodium–glucose cotransporter 2 (SGLT2)

Sodium–glucose cotransporter 2 (SGLT2) belongs to the solute carrier family SLC5A and is the main responsible for glucose reabsorption into the bloodstream after its filtration by the kidneys. In type 2 diabetes, renal glucose reabsorption is increased and contributes to hyperglycemia. The inhibition of SGLT2 diminishes the level of glucose in the blood and enhances the excretion in the urine, making it an attractive non-insulin therapeutical strategy for the treatment of type 2 diabetes.

Small-molecule SGLT2 inhibitors entered the market about a decade ago with canagliflozin by Johnson & Johnson as first-in-class. Some others have been developed since, such as AstraZeneca’s dapagliflozin and Eli Lilly and Boehringer Ingelheim’s empagliflozin. Last January, another small-molecule inhibitor by TheracosBio received FDA approval.

In a recent paper, scientists from Boehringer Ingelheim and Peking University elucidated the binding mode and structural basis on the human SGLT2 (hSGLT2) inhibition by small-molecule drugs for the first time. These insights open the way for novel, rationally designed drugs.

The scientists managed to produce the first structure of the hSGLT bound to a small-molecule inhibitor (empagliflozin), using Cryo-EM. They observed that the sugar moiety of the drug is in the sugar-substrate binding site. This can be clearly spotted by comparison with the analogous non-human structure (vSGLT) in complex with galactose (Image 1).

Image 1.On the left: 3D structure of empagliflozin, with indications on the sugar moiety and the aglycon tail. On the right: Comparison of the 3D structures of hSGLT2 in complex with the inhibitor empagliflozin (blue; PDB: 7vsi) and vSGLT2 in complex with galactose (purple; PDB: 3DH4). The sugar moiety of empagliflozin overlap with the galactose. The pictures are produced with the 3decision® software.

A deeper analysis of the binding mode of the drug with the protein shows that the sugar moiety of the molecule forms a network of polar interactions through the hydroxyl groups, and stacks with the Tyr-290 aromatic side chain. The aglycone tail of the inhibitor extends towards the extracellular side of the protein and mainly interacts through hydrophobic (ex. Val-95 and Leu-84) and aromatic contacts (Phe-98 and His-80).

Image 2. Molecular interactions between hSGLT2 and empagliflozin (cartoon and lateral residues in white, ligand in blue; PDB: 7vsi). The sugar moiety of the inhibitor stacks with Tyr-290 and makes polar contacts with Asn-75 and Glu-99. The aglycone tail forms aromatic interactions with His-80 and Phe-98 and hydrophobic contacts with several residues, for instance Leu-84 and Val-95. The interactions are automatically calculated by the 3decision® software.

The inhibitor is tightly bound to the protein through this extensive network of interactions. This locks the SGLT2 in an outward/closed conformation that prevents any motion and therefore, blocks the transport of glucose into the blood.

Thanks to these findings, we can obtain a better understanding of the structure and the inhibitory mechanism of hSGLT2 but also of other SLC5A transporters.  In the diabetes research area, these insights can support and drive the structure-based design of more efficient non-insulin anti-diabetic drugs.

Reference:

Niu, Y., Liu, R., Guan, C. et al. Structural basis of inhibition of the human SGLT2–MAP17 glucose transporter. Nature601, 280–284 (2022). https://doi.org/10.1038/s41586-021-04212-9