Sodium-Glucose Linked Transporters (SGLTs) are a family of symporters that harness the sodium gradient to drive transport of sugar across the membrane. In humans, hSGLT2 is found in the kidneys and is an important target in the treatment of type-2 diabetes. Structures are available of the bacterial homologue vSGLT in the inward-facing <i>apo</i> and substrate-bound conformations, and more recently of partially inward-open hSGLT1 and partially outward-open inhibitor (empagliflozin) bound hSGLT2, providing some insight to the transport cycle. However, many of the molecular details around the nature of substrate binding, unbinding, and how ions and substrate drive the conformational changes remain unclear. We have used molecular dynamics simulations to explore the dynamics of SGLT family transporters in different substrate-bound configurations, including weighted ensemble simulations performed using WESTPA to explore and quantify the transition landscape. In particular, we investigate the behaviour of the inner and outer gates and how the transition landscape is altered in different substrate-bound configurations. Our work furthers our understanding of how SGLTs carry out their function at the molecular level and provides key details into the mechanism of action of current drugs, which is important for future pharmaceutical developments.

Computational investigation of the transport cycle of sodium-glucose transport proteins

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ACS Fall 2022

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