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A Comparative Study on Selectivity of α-Conotoxins GI and ImI Using Their Synthetic Analogues and Derivatives

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Abstract

Comparative structure-function studies have been carried out for α-conotoxin GI acting on nicotinic acetylcholine receptors (AChR) from mammalian muscles and from the electric organ of the Torpedo californica ray and for α-conotoxin ImI, which targets the neuronal a7 AChR. A series of analogs has been prepared for this purpose: chemically modified derivatives, including a covalently linked dimer of GI, as well as analogs wherein one or several amino acid residues have been changed using solid-phase peptide synthesis. The activity of all compounds was assessed in competition with radioiodinated and/or tritiated α-conotoxin GI for binding to the membrane-bound AChR of Torpedo californica. Binding of radioiodinated α-conotoxin GI dimer was also monitored directly, revealing the largest, as compared to all other analogues, difference in the affinity between the two binding sites in the receptor (KD ∼ 11 and 1200 nM). Comparison of binding data with the results of CD measurements point to important role of the spatial organization of the α-conotoxin second loop in manifestation of their “muscle” or “neuronal” specificity.

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Authors and Affiliations

  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

    Igor E. Kasheverov, Maxim N. Zhmak, Innokenty V. Maslennikov, Yuri N. Utkin & Victor I. Tsetlin

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  1. Igor E. Kasheverov
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  2. Maxim N. Zhmak
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  3. Innokenty V. Maslennikov
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  4. Yuri N. Utkin
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  5. Victor I. Tsetlin
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Kasheverov, I.E., Zhmak, M.N., Maslennikov, I.V. et al. A Comparative Study on Selectivity of α-Conotoxins GI and ImI Using Their Synthetic Analogues and Derivatives. Neurochem Res 28, 599–606 (2003). https://doi.org/10.1023/A:1022889827195

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