Nicotinic Acetylcholine Receptor
Nicotinic Acetylcholine Receptor and Toxins from Snake Venom: Study of Ligand-Receptor Interactions
Tech Area / Field
- BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
- MED-DRG/Drug Discovery/Medicine
3 Approved without Funding
Institute of Bioorganic Chemistry, Russia, Moscow
- Barrow Neurological Institute, USA, AZ, Phoenix
Project summarythe proposed study are membranes from adrenal gland cortex and electric organ of ray Torpedo californica, recombinant extracellular domain of human alpha7 nAChR subunit and several snake neurotoxins selective for different subtypes of nAChRs. Among these toxins are recombinant analogs of long chain alpha-neurotoxins from Naja oxiana venom and weak toxin from Naja kaouthia venom.
In the project course the amino acid residues mediating ligand-receptor interactions between extracellular domain of nAChR and neurotoxins will be revealed. This knowledge should give clues to understanding the mechanisms of interaction between antagonists and pharmacologically different subtypes of nAChRs and other members of ‘cys-loop’ membrane receptors family (5-HT3 serotonin, GABA-A and glycine receptors).
High-level expression systems for production of recombinant neurotoxins and extracellular domain of nAChR (developed by the authors) permit to produce isotope-labeled analogues of these proteins for subsequent NMR investigation. Modern NMR techniques will allow us to determine the spatial structures of neurotoxins and extracellular domain of nAChR, as well as to delineate the intermolecular interactions at atomic level.
The proposed project includes the following milestones:
- optimization of bacterial expression systems for producing of “weak” neurotoxin, isotope-labeled analogues of extracellular domain of nAChR, neurotoxins and their mutants;
- identification and comparison of structural determinants of various types of neurotoxins (long and short chain alpha-neurotoxins, “weak” neurotoxin), important for interaction with different types of nAChR in order to establish relationships between the types of observed activities and the toxins structures;
- identification of the changes in the spatial structure of the extracellular nAChR domain caused by interaction with various neurotoxins.
Based on the obtained data we will suggest the algorithm of creation of synthetic selective inhibitors for different nAChR types. These results will be important not only as fundamental knowledge, but, in perspective, will be useful for elaboration of a new-type biopharmaceuticals. Thus, synthetic inhibitors of nAChRs, developed on the basis of the project results, could be used as drug prototypes for treatment of a number of diseases, including nicotinic addiction.
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