Molecular Determinants Conferring the Stoichiometric-Dependent Activity of α-Conotoxins at the Human α9α10 Nicotinic Acetylcholine Receptor Subtype

Abstract

α9α10 nicotinic acetylcholine receptors (nAChRs) putatively exist at different stoichiometries. We systematically investigated the molecular determinants of α-conotoxins Vc1.1, RgIA#, and PeIA inhibition at hypothetical stoichiometries of the human α9α10 nAChR. Our results suggest that only Vc1.1 exhibits stoichiometric-dependent inhibition at the α9α10 nAChR. The hydrogen bond between N154 of α9 and D11 of Vc1.1 at the α9(+)-α9(-) interface is responsible for the stoichiometric-dependent potency of Vc1.1.

d-Amino Acid Substitution of α-Conotoxin RgIA Identifies its Critical Residues and Improves the Enzymatic Stability

“…In various rat analgesic models, RgIA and its derivative RgIA4 have been proven to be effective antagonists, preventing neuropathic pain [11,12,13,14]. Due to its application potential, several studies have focused on the blocking molecular mechanism of RgIA, to guide the development of novel analogues [7,15,16,17]. However, the precise interaction sites of RgIA with α9α10 nAChR have not been fully characterized yet.…”

α-Conotoxin Vc1.1 Structure–Activity Relationship at the Human α9α10 Nicotinic Acetylcholine Receptor Investigated by Minimal Side Chain Replacement

“…36 component formed a hydrogen bond with D11 of Vc1.1 that is responsible for the higher sensitivity of the receptor to Vc1.1. 37,38 Despite the advancement in studying the binding mode of Vc1.1 at α9α10 nAChR based on computational modeling, understanding the structure-activity relationship of Vc1.1 with the α9α10 nAChR is hampered by the lack of high resolution crystal structures and high degree of confidence computational models of α9α10 nAChR bound to Vc1.1.…”

Synthesis and biological activity study of the retro-isomer of RhTx against TRPV1

“…Both RhTx and RL-RhTx were synthesized by solid phase peptide synthesis method using Fmoc chemistry (Fmoc SPPS). [29][30][31] Fmoc SPPS allows milder reaction conditions and low cost for peptide synthesis. 32 The versatility of the method was proved.…”