, 1997b), are buried in the 3D structure inside the tertiary stru

, 1997b), are buried in the 3D structure inside the tertiary structure or coordinated with calcium ions. In order to approach conformation-dependent motifs, our group has been using neutralizing monoclonal antibodies. Jararhagin binding to collagen I and IV generic triple-helix structure was completely

inhibited by a monoclonal antibody, MAJar 3, which recognizes a conformational epitope located on the Da sub-domain of the disintegrin-like domain (Moura-da-Silva et al., 2008). In parallel, jararhagin binding to α2β1 integrin used an additional motif present in the hyper-variable region of the cysteine-rich domain (Tanjoni et al., 2010) as suggested by previously (Serrano et al., 2007). This region is spatially distinct from the collagen-binding region, since the antibodies selleckchem that block jararhagin binding to collagen did not affect the binding of the toxin to the integrin (Tanjoni et al., 2010). The evidence that class P-III SVMPs bind to collagens and α2β1 integrin by different motifs brings new insights regarding the action of these complex molecules. The spatial independence of catalytic cleft, integrin-binding and collagen-binding

motifs (Fig. 2) indicates the possibility of assembling multi-structural complexes interposing the contacts between Natural Product Library in vitro endothelial cells and ECM, displacing the focal adhesion contacts. This hypothesis would explain endothelial cell apoptosis by anoikis induced by jararhagin (Tanjoni et al., 2005) and also the tissue localization of jararhagin around blood vessels after injection into mice Galactosylceramidase tissues, which is essential for the expression of jararhagin-induced hemorrhagic activity (Baldo et al., 2010). The therapeutic use of jararhagin and other similar SVMPs is a controversial subject. It is undeniable that the versatility of these toxins for different biological systems opens windows to medical and biotechnological applications. On the other side, the complex structure

and the presence of different pharmacologically active motifs in the same molecule make it difficult to envisage a pharmaceutical use of jararhagin as a drug. Investigations aiming to identify relevant motifs responsible for each biological interaction would allow their future use as leader structures to design new drugs as, for example, integrin antagonists. However, the relevance of conformational epitopes stressed above must be considered, and the recognition of surface-exposed conformation-dependent motifs is still essential to find out bioactive leader structures in jararhagin molecule clarifying its possible applications. Even though the therapeutic relevance of jararhagin is uncertain, this toxin could be used as a tool for studies of similar toxins, for insights into matrix biology interactions and to elucidate mechanisms related to angiogenesis and cancer. In this way, it was described that jararhagin reduced the number of lung metastasis (Corrêa et al.

This entry was posted in Uncategorized. Bookmark the permalink.

Leave a Reply

Your email address will not be published. Required fields are marked *


You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>