Glucose transport may hinge on a fleeting transition-like state

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Without glucose (red) the hill is too high to climb and so the protein (gray) cannot easily change its path along the dashed line: The light is red. Just like in enzymes, glucose has the highest affinity for the intermediate protein state (yellow), and so glucose binding (red) means the protein can take an easier path along the solid line to transport the sugar: The light is green. Credit: Claudia Alleva/Stockholm University

Stockholm University and SciLifeLab researchers have uncovered how glucose transporters move nutrients into cells, bridging a long-standing gap between structure and function in membrane biology. "Our study shows that these transport proteins rely on a previously uncharacterized intermediate state that functions much like the 'transition state' in enzyme catalysis. This is a discovery that reshapes our understanding of one of biology's most fundamental processes," says David Drew, professor of biochemistry, Department of Biochemistry and Biophysics, Stockholm University.

From molds to mammals, glucose is a primary energy source for life. To be used by cells, glucose must first enter the cell by crossing the cell's membrane, via specialized proteins known as GLUT transporters. While these proteins have long served as textbook examples for applying enzyme-like kinetics to membrane transport, scientists have struggled to reconcile structural snapshots of these transporters with how they actually function in real time.

The new research, published in Nature Structural & Molecular Biology, addresses this challenge by combining advanced spectroscopy, protein engineering, and molecular simulations to reveal how transport specificity is determined—not at the point of initial sugar binding, as previously assumed, but during a later, transient step in the transport cycle.

"Our results show that substrate specificity is governed by the ability of a sugar to stabilize a transition-like intermediate state during transport," Drew explains. "This shifts the focus away from initial binding and toward dynamic conformational changes that occur mid-transport."

The discovery provides a conceptual breakthrough by aligning the function of membrane transporters with the well-established framework of enzyme catalysis, where transition states play a central role. It also offers a new lens through which to interpret structural data and could inform future efforts to design drugs targeting glucose transporters in diseases such as cancer and diabetes.

Publication details

Do-Hwan Ahn et al, A two-step mechanism for sugar translocation, Nature Structural & Molecular Biology (2026). DOI: 10.1038/s41594-026-01784-w

Journal information: Nature Structural & Molecular Biology

Key concepts

biochemistryBiomolecular & subcellular processesTransport phenomena

Provided by Stockholm University