Lemme, Katrin. Thermodynamic evaluation of carbohydrate-lectin interactions. 2013, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10606
Most reported thermodynamic studies on carbohydrate-recognizing proteins (lectins) concern plant lectins. However, human and bacterial lectins have recently gained increasing interest. One of these, the human lectin E-selectin plays a crucial role in leukocyte trafficking and is a key player in the early stages of inflammation; it is responsible for the rolling of leukocytes along the vascular endothelial surface, which is followed by their firm adhesion and extravasation to fight the inflammatory stimulus. The interaction of E-selectin with the minimal binding epitope of its physiological ligand, the so-called sLex tetrasaccharide, and mimetic antagonists thereof are characterized by a large favorable entropy term. The entropic benefit is mainly related to the release of water molecules from the large binding interface into bulk water, as well as to the high degree of pre-organization of sLex. The replacement of those parts of sLex not involved in binding by lipophilic moieties resulted in improved binding enthalpy (chapter 2.1.1). The lectin DC-SIGN (DC-specific intracellular adhesion molecule-3 grabbing nonintegrin) plays a crucial role in the immune system and is involved in the defense mechanism against pathogens. The millimolar binding affinities of DC-SIGN antagonists are the result of a favorable enthalpic term opposed by an entropic penalty (chapter 2.1.2). In contrast, antagonists binding to Siglec-4 (MAG) and Siglec-2 (CD22), inhibitory proteins of the central nervous system and the immune system, respectively, bind with nanomolar binding affinities. The driving force for their binding results from a strong enthalpic contribution and a varying entropic term, indicating optimal exploitation of the binding pocket (chapters 2.2.1 and 2.2.2). Finally, low nanomolar binding affinities were also found for FimH antagonists. FimH antagonists prevent the initial attachment of uropathogenic Escherichia coli to host cells and therefore offer a potential therapeutic approach for the prevention and/or treatment of urinary tract infection. They exhibit favorable enthalpic contributions and are accompanied by only small entropic penalties, although some of the antagonists are equipped with highly flexible aglycones (chapter 2.3.1).
In summary, the largely differing thermodynamics of the investigated carbohydrate-lectin interactions have contributed helpful insight into the driving forces of these interactions.
|Committee Members:||Klebe, Gerhard|
|Faculties and Departments:||05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||217 Bl.|
|Last Modified:||30 Jun 2016 10:54|
|Deposited On:||28 Nov 2013 10:17|
Repository Staff Only: item control page