SFI UREKA Site in Molecular Recognition
Translating Design into Application

Molecular Design

Project 5:        Characterization of Carbohydrate Recognition and Binding in Mistletoe Lectin    

Supervisor:     Prof. Robert J. Woods, School of Chemistry

Project Summary: Lectins are sugar-binding proteins. Their biological activity is directly connected to their high affinity for specific sugar moieties, which makes them key players in molecular recognition processes. This research project focuses on Mistletoe Lectin I (ML-I or viscumin), a galactose (Gal)-specific AB-toxin from Viscum album, currently used in the treatment of cancer ^1,2. In ML-I only two binding sites are active and they are located in the a1 and g2 subdomains. The architecture of the two sites is virtually identical, except for a few residues which are not conserved. This difference has a significant impact on their relative binding affinity. A third potential binding-site has been identified in the b1 subdomain. The residue sequence of the potential b1 binding-site reflects almost identically the one of the a1 and g2 sites, except for the polar residues binding Gal, which are replaced in the b1 site by non-polar residues. Site-directed mutagenesis will be conducted to “activate” the potential b1 binding-site. Ultimately, the aim of this project is to characterize molecular recognition and to modulate sugar-binding activity and selectivity in ML-I via computer simulation techniques.

The student will work in our computational biophysics lab and will be directly supervised by Dr. Elisa Fadda, a senior research fellow in the group. The student will be responsible for setting-up and running “Molecular Docking” experiments. Based on the data obtained, he or she will use state-of-the-art statistical mechanics techniques to determine binding affinities of the a1 and g2 sites in ML-I. After identifying the key binding residues, the student will set-up site-directed mutagenesis experiments aimed at activating and modulating the affinity of the putative b1 binding site.

¹  L. Bergmann, et al. European Journal of Cancer (2008), Vol. 44 (12), pp. 1657 – 1662;

²  I.F. Pryme, et al. Histol . Histopathol. (2006), Vol. 21(3), pp. 285-299.

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