Open AccessComputational and Functional Mapping of Human and Rat α6β4 Nicotinic Acetylcholine Receptors Reveals Species-Specific Ligand-Binding Motifs
Author(s) -
Arik J. Hone,
Quentin Kaas,
Ireland Kearns,
Fuaad Hararah,
Joanna Gajewiak,
Sean Christensen,
David J. Craik,
J. Michael McIntosh
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01973
Subject(s) - nicotinic agonist , acetylcholine receptor , chemistry , receptor , pharmacology , potency , ligand (biochemistry) , conotoxin , binding site , nicotinic antagonist , biochemistry , in vitro , peptide , biology
Nicotinic acetylcholine receptors (nAChRs) are pharmacological targets for the treatment of neuropathic pain, and the α6β4 subtype has been identified as particularly promising. Rat α6β4 nAChRs are less sensitive to some ligands than the human homologue potentially complicating the use of rodent α6β4 receptors for screening therapeutic compounds. We used molecular dynamics simulations coupled with functional assays to study the interaction between α-conotoxin PeIA and α6β4 nAChRs and to identify key ligand-receptor interactions that contribute to species differences in α-conotoxin potency. Our results show that human and rat α6β4 nAChRs have distinct ligand-binding motifs and show markedly different sensitivities to α-conotoxins. These studies facilitated the creation of PeIA-5667, a peptide that shows 270-fold higher potency for rat α6β4 nAChRs over native PeIA and similar potency for the human homologue. Our results may inform the design of therapeutic ligands that target α6β4 nAChRs for the treatment of neuropathic pain.