Structural Requirements of MLD-Containing Disintegrins for Functional Interaction with α4β1 and α9β1 Integrins

Publisher Website
Google Scholar
Abstract
Three non-RGD-containing disintegrins, VLO5, EO5, and EC3, belong to the hetrodimeric family of these snake venom-derived proteins. They are potent inhibitors of certain leukocyte integrins such as α4β1, α4β7, and α9β1, and act through the MLD motif present in one of their subunits. However, the selectivity of these disintegrins to interact with integrins is related to the amino acid composition of the integrin-binding loop in the MLD-containing subunit. The most important amino acid is that preceding the MLD motif. In vitro experiments in adhesion and ELISA assays revealed that the TMLD-containing disintegrins, VLO5 and EO5, appeared to be very potent inhibitors of human α4β1 and α9β1 and less effective in inhibition of the α4β7 integrin. The reverse effect was observed for the AMLD-containing disintegrin, EC3. The data with native disintegrins were confirmed by experiments with synthetic peptides displaying TMLD and AMLD motifs. The MLD-containing disintegrins showed differential activities to inhibit human and murine α4β1 integrin. EC3 was a weaker inhibitor of human integrin, whereas VLO5 and EO5 less actively inhibited murine α4β1. These data describe a useful set of potent and selective integrin antagonists and suggest conformational requirements of human and mouse integrins for interaction with ligands.

This publication has 24 references indexed in Scilit: