Structures of human SGLT in the occluded state reveal conformational changes during sugar transport

Cui, Wenhao; Niu, Yange; Sun, Zhenli; Liu, Rui; Chen, Lei

doi:10.1038/s41467-023-38720-1

Cited by 15 publications

(7 citation statements)

References 34 publications

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“…For instance, non-LeuT-fold TMs −1 and 13 of SGLT may limit TM1a swinging (Figure 5F). TM13 of the human homologs SGLT1 and SGLT2 binds to MAP17, an essential subunit for hSGLT2 glucose uptake activity that promotes cell surface expression 26 .…”

Section: Discussionmentioning

confidence: 99%

They all rock: A systematic comparison of conformational movements in LeuT-fold transporters

Licht,

Berry,

Gutierrez

et al. 2024

Preprint

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Many membrane transporters share the LeuT fold—two five-helix repeats inverted across the membrane plane. Despite hundreds of structures, whether distinct conformational mechanisms are supported by the LeuT fold has not been systematically determined. After annotating published LeuT-fold structures, we analyzed distance difference matrices (DDMs) for nine proteins with multiple available conformations. We identified rigid bodies and relative movements of transmembrane helices (TMs) during distinct steps of the transport cycle. In all transporters the bundle (first two TMs of each repeat) rotates relative to the hash (third and fourth TMs). Motions of the arms (fifth TM) to close or open the intracellular and outer vestibules are common, as is a TM1a swing, with notable variations in the opening-closing motions of the outer vestibule. Our analyses suggest that LeuT-fold transporters layer distinct motions on a common bundle-hash rock and demonstrate that systematic analyses can provide new insights into large structural datasets.

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Section: Discussionmentioning

confidence: 99%

They all rock: A systematic comparison of conformational movements in LeuT-fold transporters

Licht,

Berry,

Gutierrez

et al. 2024

Preprint

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“…MAP17 co-expression enhances hSGLT2 activity without altering hSGLT2 expression on the cell membrane 19 . However, recent surface labeling experiments using antibodies against the extracellular domain of hSGLT2 have demonstrated that MAP17 is essential for robust surface hSGLT2 expression 34 . Although MAP17 is anticipated to induce a structural change in the active state of hSGLT2 (ref.…”

Section: Discussionmentioning

confidence: 99%

Transport and inhibition mechanism of the human SGLT2–MAP17 glucose transporter

Hiraizumi,

Akashi,

Murasaki

et al. 2023

Nat Struct Mol Biol

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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.

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“…The carriers are proteins that differ by substrate specificity, distribution, and regulatory mechanisms. Uniporters are sodium-independent, transporting glucose across the plasma membrane by facilitated diffusion (GLUTs and SWEETs) [1].…”

Section: Introductionmentioning

confidence: 99%

“…Symporters are responsible for active glucose transport against its concentration gradient; they are sodium-dependent glucose cotransporters (SGLTs) [1]. They complement pancreatic hormones (insulin and glucagon) in maintaining sugar homeostasis through blood glucose level regulation.…”

Section: Introductionmentioning

confidence: 99%

Risks and Benefits of SGLT-2 Inhibitors for Type 1 Diabetes Patients Using Automated Insulin Delivery Systems—A Literature Review

Elian,

Popovici,

Karampelas

et al. 2024

IJMS

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The primary treatment for autoimmune Diabetes Mellitus (Type 1 Diabetes Mellitus-T1DM) is insulin therapy. Unfortunately, a multitude of clinical cases has demonstrated that the use of insulin as a sole therapeutic intervention fails to address all issues comprehensively. Therefore, non-insulin adjunct treatment has been investigated and shown successful results in clinical trials. Various hypoglycemia-inducing drugs such as Metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, amylin analogs, and Sodium-Glucose Cotransporters 2 (SGLT-2) inhibitors, developed good outcomes in patients with T1DM. Currently, SGLT-2 inhibitors have remarkably improved the treatment of patients with diabetes by preventing cardiovascular events, heart failure hospitalization, and progression of renal disease. However, their pharmacological potential has not been explored enough. Thus, the substantial interest in SGLT-2 inhibitors (SGLT-2is) underlines the present review. It begins with an overview of carrier-mediated cellular glucose uptake, evidencing the insulin-independent transport system contribution to glucose homeostasis and the essential roles of Sodium-Glucose Cotransporters 1 and 2. Then, the pharmacological properties of SGLT-2is are detailed, leading to potential applications in treating T1DM patients with automated insulin delivery (AID) systems. Results from several studies demonstrated improvements in glycemic control, an increase in Time in Range (TIR), a decrease in glycemic variability, reduced daily insulin requirements without increasing hyperglycemic events, and benefits in weight management. However, these advantages are counterbalanced by increased risks, particularly concerning Diabetic Ketoacidosis (DKA). Several clinical trials reported a higher incidence of DKA when patients with T1DM received SGLT-2 inhibitors such as Sotagliflozin and Empagliflozin. On the other hand, patients with T1DM and a body mass index (BMI) of ≥27 kg/m2 treated with Dapagliflozin showed similar reduction in hyperglycemia and body weight and insignificantly increased DKA incidence compared to the overall trial population. Additional multicenter and randomized studies are required to establish safer and more effective long-term strategies based on patient selection, education, and continuous ketone body monitoring for optimal integration of SGLT-2 inhibitors into T1DM therapeutic protocol.

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Structures of human SGLT in the occluded state reveal conformational changes during sugar transport

Cited by 15 publications

References 34 publications

They all rock: A systematic comparison of conformational movements in LeuT-fold transporters

They all rock: A systematic comparison of conformational movements in LeuT-fold transporters

Transport and inhibition mechanism of the human SGLT2–MAP17 glucose transporter

Risks and Benefits of SGLT-2 Inhibitors for Type 1 Diabetes Patients Using Automated Insulin Delivery Systems—A Literature Review

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