Rational Design of α-Conotoxin Analogues Targeting α7 Nicotinic Acetylcholine Receptors
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that belong to the superfamily of Cys loop receptors. Valuable insight into the orthosteric ligand binding to nAChRs in recent years has been obtained from the crystal structures of acetylcholine-binding proteins (AChBPs) that...
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Veröffentlicht in: | The Journal of biological chemistry 2009-04, Vol.284 (14), p.9498 |
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Sprache: | eng |
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Zusammenfassung: | Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that belong to the superfamily of Cys loop receptors.
Valuable insight into the orthosteric ligand binding to nAChRs in recent years has been obtained from the crystal structures
of acetylcholine-binding proteins (AChBPs) that share significant sequence homology with the amino-terminal domains of the
nAChRs. α-Conotoxins, which are isolated from the venom of carnivorous marine snails, selectively inhibit the signaling of
neuronal nAChR subtypes. Co-crystal structures of α-conotoxins in complex with AChBP show that the side chain of a highly
conserved proline residue in these toxins is oriented toward the hydrophobic binding pocket in the AChBP but does not have
direct interactions with this pocket. In this study, we have designed and synthesized analogues of α-conotoxins ImI and PnIA[A10L],
by introducing a range of substituents on the Pro 6 residue in these toxins to probe the importance of this residue for their binding to the nAChRs. Pharmacological characterization
of the toxin analogues at the α 7 nAChR shows that although polar and charged groups on Pro 6 result in analogues with significantly reduced antagonistic activities, analogues with aromatic and hydrophobic substituents
in the Pro 6 position exhibit moderate activity at the receptor. Interestingly, introduction of a 5-( R )-phenyl substituent at Pro 6 in α-conotoxin ImI gives rise to a conotoxin analogue with a significantly higher binding affinity and antagonistic activity
at the α 7 nAChR than those exhibited by the native conotoxin. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M806136200 |