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Structural requirements of MLD-containing disintegrins for functional interaction with alpha 4 beta 1 and alpha 9 beta 1 integrins

Bazan-Socha, S., Kisiel, D. G., Young, B., Theakston, R.David G., Calvete, J. J., Sheppard, D. and Marcinkiewicz, C. (2004) 'Structural requirements of MLD-containing disintegrins for functional interaction with alpha 4 beta 1 and alpha 9 beta 1 integrins'. Biochemistry, Vol 43, Issue 6, pp. 1639-1647.

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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 alpha4beta1, alpha4beta7, and alpha9beta1, 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 alpha4beta1 and alpha9beta1 and less effective in inhibition of the alpha4beta7 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 ANILD motifs. The NILD-containing disintegrins showed differential activities to inhibit human and murine alpha4beta1 integrin. EC3 was a weaker inhibitor of human integrin, whereas VLO5 and EO5 less actively inhibited murine alpha4beta1. 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.

Item Type: Article
Uncontrolled Keywords: platelet-aggregation inhibitors eristocophis-macmahoni venom heterodimeric disintegrin cell-adhesion snake-venom alpha-v-beta-3 integrins echis-carinatus terminal domain binding-site gpiib-iiia
Subjects: QW Microbiology and Immunology > Antigens and Antibodies. Toxins and Antitoxins > QW 630 Toxins. Antitoxins
WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI):
Depositing User: Martin Chapman
Date Deposited: 26 Jul 2012 14:55
Last Modified: 06 Feb 2018 13:03


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