This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Multivalent binding events are widespread in nature and occur when multiple ligands on one entity simultaneously interact with multiple receptors on a complementary entity. This type of interaction has been demonstrated to be mechanically and functionally distinct from its monovalent alternative and is relatively commonplace in carbohydrate-mediated biological events. The best-studied manifestations of multivalency include dramatically increased functional affinities and enhanced or even switched selectivities compared with the monovalent counterpart. Clustered ligands have also been shown to facilitate receptor di- or oligomerization, which is often a prerequisite for initiating biological responses. The prospect of exploiting the cluster effect in the design of ligands with increased functional affinities has been widely investigated and successfully exploited in the synthesis of inhibitors of bacterial toxins, selectins, and in the synthesis of inhibitors of the binding of viruses to host cells. Studies by our laboratory have established a new manifestation of multivalency and demonstrate, for the first time, that bacterial sialidases which contain a catalytic domain together with one or more carbohydrate-binding domains are able to hydrolyze polyvalent substrates with much greater catalytic efficiency than monovalent counterparts. The striking difference in enzymatic activity displayed by these enzymes can be explained by invoking a model wherein the catalytic and lectin domains interact simultaneously with the polyvalent substrate. Inhibition studies have indicated that galactosyl residues revealed by the action of sialidases on polymeric substrates can serve as ligands for lectin domains. This observation has been exploited in the design of a novel and potent polyvalent inhibitor of the sialidase of Vibrio cholerae. This inhibitor is the first of its type in that it is not based on a sialic acid-related scaffold, and not only supports our hypothesis for the role of the lectin-binding domains in bacterial sialidases, but also demonstrates a simple way of engineering exquisite selectivity for inhibitors of modular enzymes that possess a catalytic domain together with one or more binding domains.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR005351-19
Application #
7721572
Study Section
Special Emphasis Panel (ZRG1-BNP (40))
Project Start
2008-02-01
Project End
2009-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
19
Fiscal Year
2008
Total Cost
$263,971
Indirect Cost
Name
University of Georgia
Department
Type
Organized Research Units
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Hannides, Angelos K; Aller, Robert C (2016) Priming effect of benthic gastropod mucus on sedimentary organic matter remineralization. Limnol Oceanogr 61:1640-1650
Revoredo, Leslie; Wang, Shengjun; Bennett, Eric Paul et al. (2016) Mucin-type O-glycosylation is controlled by short- and long-range glycopeptide substrate recognition that varies among members of the polypeptide GalNAc transferase family. Glycobiology 26:360-76
Zhao, Wujun; Zhu, Taotao; Cheng, Rui et al. (2016) Label-Free and Continuous-Flow Ferrohydrodynamic Separation of HeLa Cells and Blood Cells in Biocompatible Ferrofluids. Adv Funct Mater 26:3990-3998
Wu, Liang; Viola, Cristina M; Brzozowski, Andrzej M et al. (2015) Structural characterization of human heparanase reveals insights into substrate recognition. Nat Struct Mol Biol 22:1016-22
Qiu, Hong; Xiao, Wenyuan; Yue, Jingwen et al. (2015) Heparan sulfate modulates Slit3-induced endothelial cell migration. Methods Mol Biol 1229:549-55
Li, Zixuan; Moniz, Heather; Wang, Shuo et al. (2015) High structural resolution hydroxyl radical protein footprinting reveals an extended Robo1-heparin binding interface. J Biol Chem 290:10729-40
Czuchry, Diana; Desormeaux, Paul; Stuart, Melissa et al. (2015) Identification and Biochemical Characterization of the Novel ?2,3-Sialyltransferase WbwA from Pathogenic Escherichia coli Serotype O104. J Bacteriol 197:3760-8
Liu, Lin; Zha, Jingying; DiGiandomenico, Antonio et al. (2015) Synthetic Enterobacterial Common Antigen (ECA) for the Development of a Universal Immunotherapy for Drug-Resistant Enterobacteriaceae. Angew Chem Int Ed Engl 54:10953-7
Zhang, Fuming; Moniz, Heather A; Walcott, Benjamin et al. (2014) Probing the impact of GFP tagging on Robo1-heparin interaction. Glycoconj J 31:299-307
Zarnowski, Robert; Westler, William M; Lacmbouh, Ghislain Ade et al. (2014) Novel entries in a fungal biofilm matrix encyclopedia. MBio 5:e01333-14

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