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The Influence of Ligand Valency on Aggregation Mechanisms for Inhibiting Bacterial Toxins
Author(s) -
Sisu Cristina,
Baron Andrew J.,
Branderhorst Hilbert M.,
Connell Simon D.,
Weijers Carel A. G. M.,
de Vries Renko,
Hayes Edward D.,
Pukin Aliaksei V.,
Gilbert Michel,
Pieters Roland J.,
Zuilhof Han,
Visser Gerben M.,
Turnbull W. Bruce
Publication year - 2009
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200800550
Subject(s) - divalent , chemistry , valency , protein aggregation , ligand (biochemistry) , dynamic light scattering , biophysics , escherichia coli , biochemistry , stereochemistry , receptor , organic chemistry , biology , nanotechnology , philosophy , linguistics , materials science , nanoparticle , gene
Divalent and tetravalent analogues of ganglioside GM1 are potent inhibitors of cholera toxin and Escherichia coli heat‐labile toxin. However, they show little increase in inherent affinity when compared to the corresponding monovalent carbohydrate ligand. Analytical ultracentrifugation and dynamic light scattering have been used to demonstrate that the multivalent inhibitors induce protein aggregation and the formation of space‐filling networks. This aggregation process appears to arise when using ligands that do not match the valency of the protein receptor. While it is generally accepted that multivalency is an effective strategy for increasing the activity of inhibitors, here we show that the valency of the inhibitor also has a dramatic effect on the kinetics of aggregation and the stability of intermediate protein complexes. Structural studies employing atomic force microscopy have revealed that a divalent inhibitor induces head‐to‐head dimerization of the protein toxin en route to higher aggregates.