Glucose transporters are essential for metabolism of glucose in cells of diverse organisms from microbes to humans, exemplified by the disease-related human proteins GLUT1, 2, 3 and 4. Despite rigorous efforts, the structural information for GLUT1-4 or their homologues remains largely unknown. Here we report three related crystal structures of XylE, an Escherichia coli homologue of GLUT1-4, in complex with d-xylose, d-glucose and 6-bromo-6-deoxy-D-glucose, at resolutions of 2.8, 2.9 and 2.6 Å, respectively. The structure consists of a typical major facilitator superfamily fold of 12 transmembrane segments and a unique intracellular four-helix domain. XylE was captured in an outward-facing, partly occluded conformation. Most of the important amino acids responsible for recognition of D-xylose or d-glucose are invariant in GLUT1-4, suggesting functional and mechanistic conservations. Structure-based modelling of GLUT1-4 allows mapping and interpretation of disease-related mutations. The structural and biochemical information reported here constitutes an important framework for mechanistic understanding of glucose transporters and sugar porters in general.

Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

Piezo1 represents a prototype of eukaryotic mechanotransduction channels. The full-length 2547-residue mouse Piezo1 possesses a unique 38-transmembrane-helix (TM) topology and is organized into a three-bladed, propeller-shaped architecture, comprising a central ion-conducting pore, three peripheral blade-like structures, and three 90-Å-long intracellular beam-resembling structures that bridge the blades to the pore. However, how mechanical force and chemicals activate the gigantic Piezo1 machinery remains elusive. Here we identify a novel set of Piezo1 chemical activators, termed Jedi, which activates Piezo1 through the extracellular side of the blade instead of the C-terminal extracellular domain of the pore, indicating long-range allosteric gating. Remarkably, Jedi-induced activation of Piezo1 requires the key mechanotransduction components, including the two extracellular loops in the distal blade and the two leucine residues in the proximal end of the beam. Thus, Piezo1 employs the peripheral blade-beam-constituted lever-like apparatus as a designated transduction pathway for long-distance mechano- and chemical-gating of the pore.

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