title: Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system.
abstract: The sodium glucose cotransporter SGLT1 expressed mainly in the intestine and kidney has been explored extensively for understanding the mechanism of sugar cotransport and its inhibition by a classical competitive inhibitor, phlorizin (Pz). It has been shown that inhibition of SGLT1 by Pz involves its interaction followed by major conformational changes in the Pz binding domain (PBD) in C-terminal loop 13. However, the mechanism of Pz inhibition and its interaction with other members of SGLT is not known. In this hypothesis, we performed molecular modeling of SGLT1-loop 13 with Pz and carried out primary sequence analyses and secondary structure predictions to determine qualitatively similar PBDs in C-termini of human SGLT2-4, except for vSGLT, which contains an unstructured short C-terminus. The ranking of predictions of Pz interaction strongly agrees with the following ranking of previously reported Pz inhibition: SGLT2>SGLT1>SGLT4>SGLT3>>vSGLT. In addition, the sugar binding residues were found to be quite conserved among all SGLT members investigated here. Based on these preliminary analyses, we propose that other Pz-sensitive SGLTs are also inhibited via mechanism similar to SGLT1 where an aglucone of Pz, phloretin, interacts with PBD and glucoside moiety with sugar binding residues. Our hypothesis sets the stage for future analyses on investigation of Pz interaction with SGLT family and further suggests that Pz modeling may be explored to design novel inhibitors targeting several SGLT members.
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany; Department of Molecular Structure and Function, The Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada. Electronic address: mobeen.raja@sickkids.ca.
authors.forename: Mobeen
authors.initials: M
authors.lastname: Raja
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany. Electronic address: rolf.kinne@mpi-dortmund.mpg.de.
authors.forename: Rolf K H
authors.initials: RK
authors.lastname: Kinne
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010695:Phlorhizin / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014736:Vibrio parahaemolyticus
chemical_list: D001426:Bacterial Proteins; D051269:Sodium-Glucose Transporter 1; D010695:Phlorhizin
keywords: C-terminal loop 13; Modeling; Phlorizin binding domain; SGLT inhibition; SGLT2 inhibitors; Sodium glucose cotransporter SGLT1