Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
Nature. 2022 Jan;601(7892):274-279. doi: 10.1038/s41586-021-04211-w. Epub 2021 Dec 8.
Glucose is a primary energy source in living cells. The discovery in 1960s that a sodium gradient powers the active uptake of glucose in the intestine heralded the concept of a secondary active transporter that can catalyse the movement of a substrate against an electrochemical gradient by harnessing energy from another coupled substrate. Subsequently, coupled Na/glucose transport was found to be mediated by sodium-glucose cotransporters (SGLTs). SGLTs are responsible for active glucose and galactose absorption in the intestine and for glucose reabsorption in the kidney, and are targeted by multiple drugs to treat diabetes. Several members within the SGLT family transport key metabolites other than glucose. Here we report cryo-electron microscopy structures of the prototypic human SGLT1 and a related monocarboxylate transporter SMCT1 from the same family. The structures, together with molecular dynamics simulations and functional studies, define the architecture of SGLTs, uncover the mechanism of substrate binding and selectivity, and shed light on water permeability of SGLT1. These results provide insights into the multifaceted functions of SGLTs.
葡萄糖是活细胞的主要能量来源。20 世纪 60 年代发现，钠梯度为肠道中葡萄糖的主动摄取提供动力，这预示着一种继发性主动转运体的概念，它可以利用来自另一种偶联底物的能量来催化底物逆电化学梯度的运动。随后，发现耦合的 Na/葡萄糖转运是由钠-葡萄糖协同转运蛋白（SGLTs）介导的。SGLTs 负责肠道中葡萄糖和半乳糖的主动吸收，以及肾脏中葡萄糖的重吸收，并且是多种治疗糖尿病药物的作用靶点。SGLT 家族中的几个成员还转运除葡萄糖以外的关键代谢物。本文报道了原型人源 SGLT1 以及来自同一家族的相关单羧酸转运蛋白 SMCT1 的冷冻电镜结构。这些结构，以及分子动力学模拟和功能研究，定义了 SGLTs 的结构，揭示了底物结合和选择性的机制，并阐明了 SGLT1 的水通透性。这些结果为 SGLTs 的多方面功能提供了深入了解。
