Inhibitor Binding Mode and Allosteric Regulation of Na-glucose Symporters

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Dec 12

PMID 30532032

Citations 30

Authors

Paola Bisignano

Chiara Ghezzi

Hyunil Jo

Nicholas F Polizzi

Thorsten Althoff

Chakrapani Kalyanaraman

Rosmarie Friemann

Matthew P Jacobson

Ernest M Wright

Michael Grabe

Affiliations

Soon will be listed here.

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.

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