PT - JOURNAL ARTICLE AU - Tânia Filipa Custódio AU - Peter Aasted Paulsen AU - Kelly May Frain AU - Bjørn Panyella Pedersen TI - Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family AID - 10.26508/lsa.202000858 DP - 2021 Apr 01 TA - Life Science Alliance PG - e202000858 VI - 4 IP - 4 4099 - https://www.life-science-alliance.org/content/4/4/e202000858.short 4100 - https://www.life-science-alliance.org/content/4/4/e202000858.full SO - Life Sci. Alliance2021 Apr 01; 4 AB - The human glucose transporters GLUT1 and GLUT3 have a central role in glucose uptake as canonical members of the Sugar Porter (SP) family. GLUT1 and GLUT3 share a fully conserved substrate-binding site with identical substrate coordination, but differ significantly in transport affinity in line with their physiological function. Here, we present a 2.4 Å crystal structure of GLUT1 in an inward open conformation and compare it with GLUT3 using both structural and functional data. Our work shows that interactions between a cytosolic “SP motif” and a conserved “A motif” stabilize the outward conformational state and increases substrate apparent affinity. Furthermore, we identify a previously undescribed Cl− ion site in GLUT1 and an endofacial lipid/glucose binding site which modulate GLUT kinetics. The results provide a possible explanation for the difference between GLUT1 and GLUT3 glucose affinity, imply a general model for the kinetic regulation in GLUTs and suggest a physiological function for the defining SP sequence motif in the SP family.