The Clostridial neurotoxins, botulinum and tetanus, gain entry into neural cells by protein recognition involving cell specific binding sites. We are currently studying the C fragment of the tetanus toxin (the targeting domain) and the ganglioside it binds to on the cell surface. A series of prospective ligands that bind to two sites on the C fragment near the ganglioside binding site were identified by computational """"""""docking"""""""". We are using electrospray mass spectrometry to screen the ligands and identify those that actually bind to this domain of the toxin. Once we have identified various protein/ligand interactions by mass spectrometry, more detailed experiments can be designed to determine binding constants and map the neighboring amino acids in the interacting regions. The ultimate goal of this research is the synthesis of a tridentate ligand which could compete with and obstruct the ganglioside binding site, acting as a possible inhibitor of the toxin. Future experiments would examine the structure of the toxin/ganglioside complex and characterize its pore forming properties. The basic research aspect of this study will provide an understanding of the role non covalent interactions play in molecular recognition, a process critical for normal cell function and one frequently exploited by bacteria and viruses to facilitate their entrance into cells.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001614-18
Application #
6120276
Study Section
Project Start
1999-03-01
Project End
2000-02-29
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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