Topsy-turvy binding of negatively charged homogalacturonan oligosaccharides to galectin-3

Yi Zheng, Jiyong Su, Michelle C. Miller, Jie Geng, Xuejiao Xu, Tao Zhang, Maksim Mayzel, Yifa Zhou, Kevin H. Mayo, Guihua Tai

Research output: Contribution to journalArticlepeer-review


Galectin-3 is crucial to many physiological and pathological processes. The generally accepted dogma is that galectins function extracellularly by binding specifically to β(1→4)-galactoside epitopes on cell surface glycoconjugates. Here, we used crystallography and NMR spectroscopy to demonstrate that negatively charged homogalacturonans (HG, linear polysaccharides of α(1→4)-linked-D-galacturonate (GalA)) bind to the galectin-3 carbohydrate recognition domain. The HG carboxylates at the C6 positions in GalA rings mandate that this saccharide bind galectin-3 in an unconventional, "topsy-turvy"orientation that is flipped by about 180o relative to that of the canonical β-galactoside lactose. In this binding mode, the reducing end GalA β-anomer of HGs takes the position of the nonreducing end galactose residue in lactose. This novel orientation maintains interactions with the conserved tryptophan and seven of the most crucial lactose-binding residues, albeit with different H-bonding interactions. Nevertheless, the HG molecular orientation and new interactions have essentially the same thermodynamic binding parameters as lactose. Overall, our study provides structural details for a new type of galectin-sugar interaction that broadens glycospace for ligand binding to Gal-3 and suggests how the lectin may recognize other negatively charged polysaccharides like glycoaminoglycans (e.g. heparan sulfate) on the cell surface. This discovery impacts on our understanding of galectin-mediated biological function.

Original languageEnglish (US)
Pages (from-to)341-350
Number of pages10
Issue number3
StatePublished - Mar 1 2021
Externally publishedYes

Bibliographical note

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© 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail:


  • NMR
  • crystallography
  • galectin
  • oligosaccharide
  • protein


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