Structural and functional characterization of sugar transporters in health and disease

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 DESCRIPTION (provided by applicant): Glucose is a ubiquitous cellular fuel source in virtually all organisms. In addition to its energetic role in the human body, glucose also serves as a critical metabolic intermediate in which activated glucose molecules are transported to the ER and Golgi and used for glycosylating proteins, lipids and polysaccharides as part of the biosynthetic-secretory pathway. The path of entry to the body is common for glucose and the other dietary monosaccharides, which are absorbed by enterocytes of the small intestine and distributed throughout the body in the bloodstream. The plasma glucose concentration is tightly maintained by hormonal control and conserved reabsorption mechanisms in the kidneys. Secondary active transporters facilitate these absorption/reabsorption processes as well as the exclusive delivery of activated glucose molecules to the ER and Golgi. Alterations in their inherent functions result in numerous human diseases and disorders, such as type II diabetes; thus, an intricate understanding of their structure and dynamics is a critical objective for biomedical research. During the original grant cycle, we solved the first crystal structure for an member of the sodium glucose transporter family, the Vibrio parahaemolyticus sodium/galactose symporter (vSGLT). On the subsequent renewal, we solved additional structures of the inward-open conformation of vSGLT, which in conjunction with biochemical and molecular dynamics simulations reveals the mechanism allowing substrate release. These two distinct conformations obtained during the course of this grant have fundamentally advanced our understanding of membrane transport to an atomic level and are the foundation for this competitive renewal. In addition, we aim to resolve mammalian transporters (in particular Homo sapiens) of SGLT (SLC5 family) as well as a distinct, and as of yet structurally unresolved class of nucleotide sugar transporters, the SLC35 family. The aims of this renewal are: Aim 1 captures a complete transport cycle for vSGLT using double electron-electron resonance and wide-angle x-ray scattering. Aims 2 and 3 structurally resolve two classes of human transporters with pharmaceutical relevance, the Solute Sodium Symporter family (SLC5) and the Nucleotide Sugar Transporters family (SLC35). Elucidating the structural basis for these transport families will increase our understanding of the related diseases and aid in drug development.