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Toxins 2011, 3(11), 1393-1404; doi:10.3390/toxins3111393

Molecular Conversion of Muscarinic Acetylcholine Receptor M5 to Muscarinic Toxin 7 (MT7)-Binding Protein

Department of Biosciences, Biochemistry, Åbo Akademi University, Tykistökatu 6, FIN-20520 Turku, Finland
Author to whom correspondence should be addressed.
Received: 19 September 2011 / Revised: 11 October 2011 / Accepted: 3 November 2011 / Published: 11 November 2011
(This article belongs to the Special Issue Snake Venoms)
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Muscarinic toxin 7 (MT7) is a mamba venom peptide that binds selectively to the M1 muscarinic acetylcholine receptor. We have previously shown that the second (ECL2) and third (ECL3) extracellular loops of the M1 receptor are critically involved in binding the peptide. In this study we used a mutagenesis approach on the M5 subtype of the receptor family to find out if this possesses a similar structural architecture in terms of toxin binding as the M1 receptor. An M5 receptor construct (M5-E175Y184E474), mutated at the formerly deciphered critical residues on ECL2 and 3, gained the ability to bind MT7, but with rather low affinity as determined in a functional assay (apparent Ki = 24 nM; apparent Ki for M1 = 0.5 nM). After screening for different domains and residues, we found a specific residue (P179 to L in M5) in the middle portion of ECL2 that was necessary for high affinity binding of MT7 (M5-EL179YE, apparent Ki = 0.5 nM). Mutation of P179 to A confirmed a role for the leucine side chain in the binding of MT7. Together the results reveal new binding interactions between receptors and the MT7 peptide and strengthen the hypothesis that ECL2 sequence is of utmost importance for MT binding to muscarinic receptors. View Full-Text
Keywords: G protein-coupled receptor; muscarinic toxin; acetylcholine receptor; ligand binding G protein-coupled receptor; muscarinic toxin; acetylcholine receptor; ligand binding

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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Rondinelli, S.; Näreoja, K.; Näsman, J. Molecular Conversion of Muscarinic Acetylcholine Receptor M5 to Muscarinic Toxin 7 (MT7)-Binding Protein. Toxins 2011, 3, 1393-1404.

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