Structural Basis for α-Conotoxin Potency and Selectivity

Matt Turner, Boise State University
Seth Eidemiller, Boise State University
Bryan Martin, Boise State University
Andrew Narver, Boise State University
Joshua Marshall, Boise State University
Kenneth A. Cornell, Boise State University
Owen M. McDougal, Boise State University

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This is an author-produced, peer-reviewed version of this article. The final, definitive version of this document can be found online on the Bioorganic & Medicinal Chemistry (doi: 10.1016/j.bmc.2009.07.005 ) published by Elsevier. Copyright restrictions may apply. .

Abstract

Parkinson’s disease is a debilitating movement disorder characterized by altered levels of α₆β₂* nicotinic acetylcholine receptors (nAChRs) localized on presynaptic striatal catecholaminergic neurons. α-Conotoxin MII (α-CTx MII) is a highly useful ligand to probe α₆ß₂ nAChRs structure and function, but it does not discriminate among closely related α₆* nAChR subtypes. Modification of the α-CTx MII primary sequence led to the identification of α-CTx MII[E11A], an analog with 500-5300 fold discrimination between α₆* subtypes found in both human and non-human primates. α-CTx MII[E11A] binds most strongly (femtomolar dissociation constant) to the high affinity α₆* nAChR, a subtype that is selectively lost in Parkinson's disease. Here we present the three-dimensional solution structure for α-CTx MII[E11A] as determined by two-dimensional 1H NMR spectroscopy to 0.13 +/- 0.09 Ǻ backbone and 0.45 +/- 0.08 Ǻ heavy atom root mean square deviation from mean structure. Structural comparisons suggest that the increased hydrophobic area of α-CTx MII[E11A] relative to other members of the α-CTx family may be responsible for its exceptionally high affinity for α₆α₄β₂* nAChR as well as discrimination between α₆ß₂ and α₃β₂ containing nAChRs. This finding may enable the rational design of novel peptide analogs that demonstrate enhanced specificity for α₆* nAChR subunit interfaces and provide a means to better understand nAChR structural determinants that modulate brain dopamine levels and the pathophysiology of Parkinson's disease.