Inhibitor binding mode and allosteric regulation of Na+-glucose symporters

Paola Bisignano, Chiara Ghezzi, Hyunil Jo, Nicholas F. Polizzi, Thorsten Althoff, Chakrapani Kalyanaraman, Rosmarie Friemann, Matthew P. Jacobson, Ernest M. Wright () and Michael Grabe ()
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Paola Bisignano: University of California
Chiara Ghezzi: David Geffen School of Medicine at UCLA
Hyunil Jo: University of California
Nicholas F. Polizzi: University of California
Thorsten Althoff: David Geffen School of Medicine at UCLA
Chakrapani Kalyanaraman: University of California
Rosmarie Friemann: Centre for Antibiotic Resistance (CARe) at University of Gothenburg
Matthew P. Jacobson: University of California
Ernest M. Wright: David Geffen School of Medicine at UCLA
Michael Grabe: University of California

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. 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. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5.

Date: 2018
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DOI: 10.1038/s41467-018-07700-1

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