Molecular Dynamics Simulations of the Human Glucose Transporter GLUT1

• Published in: PloS one Vol. 10; no. 4; p. e0125361
• Main Author: Park, Min-Sun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.04.2015; Public Library of Science (PLoS)
• Subjects: Amino acids; Analysis; Binding Sites; Biochemistry; Biological Transport; Blood glucose; Cardiovascular diseases; Chemical properties; Computer simulation; Conformation; Coronary artery disease; Crystal structure; Cytoplasm; Diabetes mellitus; E coli; Glucose; Glucose - metabolism; Glucose transport; Glucose transporter; Glucose Transporter Type 1 - chemistry; Glucose Transporter Type 1 - metabolism; Heart diseases; Helices; Homology; Humans; Intracellular; Ligands; Membranes; Molecular dynamics; Molecular Dynamics Simulation; Molecular interactions; Mutagenesis; Next-generation sequencing; Permease; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Residues; Structural Homology, Protein; Substrate Specificity; Substrates; Sugar; Water - metabolism; Xylose
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0125361

Glucose transporters (GLUTs) provide a pathway for glucose transport across membranes. Human GLUTs are implicated in devastating diseases such as heart disease, hyper- and hypo-glycemia, type 2 diabetes and cancer. The human GLUT1 has been recently crystalized in the inward-facing open conformation. However, there is no other structural information for other conformations. The X-ray structures of E. coli Xylose permease (XylE), a glucose transporter homolog, are available in multiple conformations with and without the substrates D-xylose and D-glucose. XylE has high sequence homology to human GLUT1 and key residues in the sugar-binding pocket are conserved. Here we construct a homology model for human GLUT1 based on the available XylE crystal structure in the partially occluded outward-facing conformation. A long unbiased all atom molecular dynamics simulation starting from the model can capture a new fully opened outward-facing conformation. Our investigation of molecular interactions at the interface between the transmembrane (TM) domains and the intracellular helices (ICH) domain in the outward- and inward-facing conformation supports that the ICH domain likely stabilizes the outward-facing conformation in GLUT1. Furthermore, inducing a conformational transition, our simulations manifest a global asymmetric rocker switch motion and detailed molecular interactions between the substrate and residues through the water-filled selective pore along a pathway from the extracellular to the intracellular side. The results presented here are consistent with previously published biochemical, mutagenesis and functional studies. Together, this study shed light on the structure and functional relationships of GLUT1 in multiple conformational states.