Scientists Uncover Atomic Structure of Key Human Glucose Transporter and Its Inhibitor

Atomic Structure of Glucose Transporter Revealed

Scientists have successfully determined the atomic-level structure of the human glucose-6-phosphate transporter (G6PT) using cryo-electron microscopy, according to research published in Nature Communications. The breakthrough study provides the first detailed look at how this crucial metabolic transporter functions and how mutations cause glycogen storage disease type 1b (GSD-1b), potentially opening new avenues for therapeutic development.

Atomic Structure of Glucose Transporter Revealed
Transport Mechanism and Key Interactions
Inhibition Mechanism Uncovered
Disease Mutations and Therapeutic Implications
Evolutionary Connections and Transport Dynamics

Transport Mechanism and Key Interactions

The research team reportedly captured G6PT in three different states: empty (apo), bound to its natural substrate glucose-6-phosphate (G6P), and bound to the inhibitor chlorogenic acid (CHA). Analysis indicates the transporter adopts the classic Major Facilitator Superfamily fold with 12 transmembrane helices organized into two domains. When empty or releasing G6P, sources indicate the structure remains in an outward-open conformation facing the endoplasmic reticulum lumen.

Structural analysis revealed two specific binding subsites for G6P recognition. According to the report, subsite A recognizes the phosphate group through interactions with residues Y60, K64, and H366, while subsite B recognizes the glucose moiety through residues W138, S142, Y233, and additional interactions with H366. Mutational studies confirmed these residues are critical for transport function, with some mutations reducing activity by 70% or more.

Inhibition Mechanism Uncovered

The study provides the first structural evidence of how chlorogenic acid inhibits G6PT function. Unlike the outward-open conformations observed with G6P, the inhibitor-bound structure shows G6PT in an inward-occluded state with the luminal gate completely closed. Researchers suggest CHA positions itself vertically in the binding pocket, with its quinic acid moiety mimicking G6P’s phosphate group and occupying similar interaction sites.

Key residues W138 and N354 were identified as crucial for CHA inhibition potency. Mutating these residues reportedly reduced inhibitor effectiveness dramatically, with N354A requiring concentrations above 20 mM to achieve only 20% inhibition compared to 45 μM for the wild-type transporter. The structural data also reveals an empty cavity near the inhibitor-binding site that could accommodate optimized drug derivatives.

Disease Mutations and Therapeutic Implications

The research team analyzed how GSD-1b-related mutations disrupt G6PT function at the molecular level. Pathogenic mutations W118R and W118C were found to almost completely abolish transport activity, while mutation S385R likely disrupts hydrogen-bond networks that stabilize the transporter during conformational changes. These findings provide mechanistic explanations for how specific genetic mutations cause disease.

Structural analysis suggests that CHA derivatives S3483 and S4048, which are reportedly 2-3 orders of magnitude more potent than CHA, could fit into the identified cavities and establish additional interactions with the transporter. This insight could accelerate the development of more effective inhibitors for therapeutic applications.

Evolutionary Connections and Transport Dynamics

The study also uncovered evolutionary relationships between human G6PT and bacterial transporters. Despite poor structural superposition, analysis indicates the phosphate recognition mechanism is conserved between human G6PT and E. coli glycerol-3-phosphate transporter, suggesting evolutionary conservation of phosphate transport mechanisms.

Comparison between the outward-open and inward-occluded structures reveals a rigid body-like motion during transport, with the N-domain swinging approximately 50° between states. This observation aligns with the rocker-switch mechanism common to MFS transporters and provides fundamental insights into how G6PT facilitates glucose-6-phosphate transport across the endoplasmic reticulum membrane.

References

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