Structural basis for α-conotoxin potency and selectivity

• Published in: Bioorganic & medicinal chemistry 2009-08, Vol.17 (16), p.5894-5899
• Main Authors: Turner, Matt, Eidemiller, Seth, Martin, Bryan, Narver, Andrew, Marshall, Joshua, Zemp, Logan, Cornell, Kenneth A., McIntosh, J.M., McDougal, Owen M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Conotoxin; Conotoxins - chemistry; Conotoxins - pharmacology; Humans; Medical sciences; Molecular Conformation; Molecular Sequence Data; Neuropharmacology; Nicotinic acetylcholine receptor; Nicotinic Antagonists - chemistry; Nicotinic Antagonists - pharmacology; NMR solution structure; Parkinson Disease - physiopathology; Parkinson’s disease; Pharmacology. Drug treatments; Protein Binding; Protein Isoforms; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.07.005

This manuscript provides the solution structure of α-conotoxin MII[E11A] and compares surface electrostatic maps for α-conotoxins that selectively inhibit α3β2 versus α6β2 nAChRs. Parkinson’s disease is a debilitating movement disorder characterized by altered levels of α 6β 2∗ (∗ indicates the possible presence of additional subunits) nicotinic acetylcholine receptors (nAChRs) localized on presynaptic striatal catecholaminergic neurons. α-Conotoxin MII (α-CTx MII) is a highly useful ligand to probe α 6β 2 nAChRs structure and function, but it does not discriminate among closely related α 6∗ 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 α 6∗ subtypes found in both human and non-human primates. α-CTx MII[E11A] binds most strongly (femtomolar dissociation constant) to the high affinity α 6 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 α 6β 2 and α 3β 2 containing nAChRs. This finding may enable the rational design of novel peptide analogs that demonstrate enhanced specificity for α 6∗ 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.