Atomistic Insights into Anomeric and Stereochemical Effects on Glucose Transport by GLUTs

TL;DR

This study reveals how glucose transporters prefer different glucose forms, showing that their binding sites have complex interactions that affect transport rates.

Contribution

The study provides new mechanistic insights into the anomeric and stereochemical preferences of GLUT1 and GLUT3 for glucose transport.

Findings

GLUT3 residues prefer α-d-glucose in extracellular regions and β-d-glucose in inward-facing regions.

Anomeric stereoselectivity involves multiple extramembranous residues, not just the central binding site.

Allosteric interactions contribute to cooperative transport behavior in mixed glucose simulations.

Abstract

Although β-glucose
is more abundant than α-glucose
in aqueous solution, GLUT3 preferentially binds α-glucose due
to favorable interactions and conformational complementarity within
the protein binding site. This study explores the anomeric preferences
of glucose transporters GLUT1 and GLUT3 for α- and β-glucose
using classical MD, providing mechanistic insight into previously
reported differences in anomer-specific transport rates during net
influx, efflux, and exchange flux, as well as asymmetric binding of
glucose anomer derivatives. Analysis of hydrogen-bonding frequencies
between glucose anomers and transporter residues, combined with root
mean squared fluctuations (RMSF) of these residues during flooding
simulations, using either mixed α/β-glucose trajectories
or single-anomer trajectories, reveals distinct residue preferences
along the transport pathway. GLUT3 residues exposed to the extracellular
solution preferentially interact with α-d-glucose,
while inward-facing residues show a bias toward β-d-glucose. This distributed network of anomer-selective interactions,
particularly concentrated in extramembranous surface regions, highlights
previously unrecognized complexity in GLUT stereoselectivity. Enhanced
residue displacements adjacent to orthosteric glucose collision sites
suggest that allosteric intra- and interchain interactions may contribute
to the cooperative transport behavior observed in mixed α +
β-glucose simulations compared to single-anomer conditions.
Importantly, anomeric stereoselectivity in GLUT1 and GLUT3 is not
confined to the central high-affinity binding site, but also involves
a multiplicity of extramembranous residues, underscoring the broader
structural basis for selective glucose transport.

Figures