School of Biological Sciences Seminar Series

From import of sialic acid across bacterial cell membranes to inhibitor binding modes of human sodium glucose transporters


Rosemarie Friemann, Erskine Visitor


Centre for Antibiotic Resistance Research at University of Gothenburg, Sweden

Time & Place

Tue, 12 Mar 2019 12:00:00 NZDT in WEST Building Rom 213A

All are welcome


Mammalian cell surfaces are decorated with complex glycoconjugates that terminate with negatively charged sialic acids. Commensal and pathogenic bacteria that colonize heavily sialylated niches (e.g. the mammalian respiratory tract and gut) can scavenge sialic acids from their surrounding environment. Scavenged sialic acid is used as a carbon, nitrogen and energy source, or to evade the host immune response by decorating their outer surfaces in sialic acid. Our work investigates the sodium sialic acid symporter (SiaT) from Proteus mirabilis (PmSiaT)1 and Staphylococcus aureus (SaSiaT)2. SiaT is a secondary active transporter of the sodium solute symporter (SSS) family, which use Na+ gradients to drive the uptake of sialic acids. We recently reported the high-resolution (1.95 Å) structure of PmSiaT.1 PmSiaT adopts the LeuT-fold and is in an outward-open conformation in complex with the sialic acid N-acetylneuraminic acid and two Na+ ions. Structural and biochemical analyses elucidate essential transport residues, and for the first time a sialic acid transporter has been characterized. Molecular modeling and molecular dynamics simulations provide insight into the transport mechanism employed by SiaT. Solute sodium symporters are a large family of proteins that cotransport Na+ with sugars, amino acids, inorganic ions or vitamins. Examples of members of this family include glucose (SGLT) and iodide (NIS) symporters. Based on the PmSiaT structure, we have developed structural models of human SGLT1 and SGLT2 in complex with inhibitors by combining computational and  functional studies3. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding.

1. Wahlgren YW, Dunevall E, North R, Paz A, Scalise MF, Bisignano P, Goyal P, Cleasson E, Bengtsson-Palme J, Carlsson RC, Andersson R, Beis K, Farewell A, Dobson R, Pochini L, Grabe M, Indiveri C, Abramson J, Ramaswamy S, Friemann R, Substrate-bound structure of a Na+- coupled sialic acid symporter reveals a new Na+ site, Nature Commun, 1;9(1):1753, doi: 10.1038/s41467-018-04045-7 (2018).
2. North RA, Wahlgren WY, Remus DM, Scalise MF, Kessans SA, Dunevall E, Soares da Costa TP, Perugini MA, Ramaswamy S, Allison JM, Indiveri C, Friemann R, Dobson RCJ, The sodium sialic acid symporter from Staphylococcus aureus has altered substrate specificity, Front Chem, doi: 10.3389/fchem.2018.00233 (2018).
3. Bisignano P,Ghezzi C, Jo H, Polizzi N, Thorsten A, Kalyanaraman C, Friemann R, Jacobson MP, Wright EM, Grabe M, Inhibitor binding mode and allosteric regulation of Na+-glucose symporters, Nature Comm, 9(1):5245, doi: 10.1038/s41467-018-07700-1 (2018).
Introduced by Ren Dobson