TY - JOUR T1 - Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202000858 VL - 4 IS - 4 SP - e202000858 AU - Tânia Filipa Custódio AU - Peter Aasted Paulsen AU - Kelly May Frain AU - Bjørn Panyella Pedersen Y1 - 2021/04/01 UR - https://www.life-science-alliance.org/content/4/4/e202000858.abstract N2 - 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. ER -