title: Mechanistic Study of Human Glucose Transport Mediated by GLUT1.
abstract: The glucose transporter 1 (GLUT1) belongs to the major facilitator superfamily (MFS) and is responsible for the constant uptake of glucose. However, the molecular mechanism of sugar transport remains obscure. In this study, homology modeling and molecular dynamics (MD) simulations in lipid bilayers were performed to investigate the combination of the alternate and multisite transport mechanism of glucose with GLUT1 in atomic detail. To explore the substrate recognition mechanism, the outward-open state human GLUT1 homology model was generated based on the template of xylose transporter XylE (PDB ID: 4GBZ), which shares up to 29% sequence identity and 49% similarity with GLUT1. Through the MD simulation study of glucose across lipid bilayer with both the outward-open GLUT1 and the GLUT1 inward-open crystal structure, we investigated six different conformational states and identified four key binding sites in both exofacial and endofacial loops that are essential for glucose recognition and transport. The study further revealed that four flexible gates consisting of W65/Y292/Y293-M420/TM10b-W388 might play important roles in the transport cycle. The study showed that some side chains close to the central ligand binding site underwent larger position changes. These conformational interchanges formed gated networks within an S-shaped central channel that permitted staged ligand diffusion across the transporter. This study provides new inroads for the understanding of GLUT1 ligand recognition paradigm and configurational features which are important for molecular, structural, and physiological research of the MFS members, especially for GLUT1-targeted drug design and discovery.
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University , Tianjin, 300072, P. R. China.
authors.forename: Xuegang
authors.initials: X
authors.lastname: Fu
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University , Tianjin, 300072, P. R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University , Tianjin, 300072, P. R. China.
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University , Tianjin, 300072, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Concordia International School , 999 Mingyue Road, Shanghai, 201206, P. R. China.
authors.forename: Daisy
authors.initials: D
authors.lastname: Zhang-Negrerie
authors.affiliation: National Supercomputing Center in Tianjin , TEDA Service Outsourcing Industrial Park, Binhai New Area, Tianjin, 300457, P. R. China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Jian
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University , Tianjin, 300072, P. R. China.|Tianjin University Collaborative Innovation Center of Chemical Science and Engineering , Tianjin, 300072, P. R. China.
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Gao
mesh_terms: D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D006801:Humans; D008051:Lipid Bilayers; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation
chemical_list: D051272:Glucose Transporter Type 1; D008051:Lipid Bilayers; C495677:SLC2A1 protein, human; D005947:Glucose