How three-finger-fold toxins interact with various cholinergic receptors.
Three-finger-fold toxins, isolated from various snake venoms, are recognized by high affinity and various specificities by different nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs, respectively) present in peripheral, as well as central, nervous systems (Karlsson et al., 2000; Servent and Ménez, 2001; Nirthanan and Gwee, 2004). The goal of our studies is (1) to identify, at the molecular level, the functional determinants involved in the various interaction profiles of nicotinic or muscarinic toxins on their respective receptors subtypes, (2) to model some of these toxin-receptor complexes using distance constraints obtained from cycle-mutant experiments, and (3) to understand how a unique scaffold (the three-finger fold) is able to support these different functional profiles and how molecular determinants have been selected during the evolution process to create these different specific properties. Finally, these structure/function analyses should be exploited to engineer non-natural peptides with new binding and functional properties useful as pharmacological tools or therapeutic agents.
Fruchart-Gaillard
Carole
C
Département d'Ingénierie et d'Etudes des Protéines, CEA, CEN Saclay, 91191 Gif-sur-Yvette, France.
Mourier
Gilles
G
Marquer
Catherine
C
Ménez
André
A
Servent
Denis
D
D000818:Animals; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009420:Nervous System / Q000187:drug effects; D009424:Nervous System Physiological Phenomena; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D012910:Snake Venoms / Q000633:toxicity*
D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D012910:Snake Venoms