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(The FASEB Journal. 2006;20:A244)
© 2006 FASEB
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170.4

Structural insights into competitive and non-competitive nicotinic antagonists

Meghan T. Miller1, Scott B. Hansen1, J. Michael McIntosh2, Baldomero M. Olivera2 and Palmer Taylor1

1 Department of Pharmacology, University of California, San Diego, 9500 Gilman Dr., La Jolla, Ca, 92093,
2 Department of Biology, University of Utah, 257 S 1400 E, Salt Lake City, UT, 84112

ABSTRACT

Nicotinic acetylcholine receptors (nAChR) undergo conformational changes that allosterically trigger opening of the ion channel. Conus peptide toxins bind with receptor subtype specificity to nAChRs. In particular {alpha}-conotoxin ImI binds selectively to the {alpha}7 nAChR subtype. Using the soluble acetylcholine binding proteins (AChBP) from Aplysia californica and Lymnaea stagnalis, we recently showed {alpha}-conotoxin ImI to be selective for the Aplysia protein. We previously solved the crystal structure of {alpha}-conotoxin ImI bound to Aplysia AChBP. Using this model we have identified regions on the apical and membrane side of the competitive binding pocket, which contribute to species specificity. Using site-directed mutagenesis we partially rescued {alpha}-conotoxin ImI binding in the Lymnaea protein. The two Conus peptides, {alpha}-conotoxins ImI and ImII, differ by only 3 of 11 amino acids, yet they appear to bind to distinct sites on the human {alpha}7 nicotinic acetylcholine receptor (nAChR). Additionally, we are exploring techniques for investigating association of {alpha}-conotoxin ImII with AChBP, thereby distinguishing its binding parameters and sites from {alpha}-conotoxin ImI.

(Supported by R37-GM18360, T32_GM07752, and Tobacco-Related Disease Research Program 12DT-0013)





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