From Crystal Structures of RgIA4 in Complex with Ac-AChBP to Molecular Determinants of Its High Potency of α9α10 nAChR

alpha 9-containing nicotinic acetylcholine receptors (nAChRs) have been shown to play critical roles in neuropathic pain. The alpha-conotoxin (alpha-CTx) RgIA and its analog RgIA4 were identified as the most selective inhibitor of alpha 9 alpha 10 nAChR. However, the mechanism of their selectivity toward alpha 9 alpha 10 nAChR remains elusive. Here, we reported the co-crystal structure of RgIA and RgIA4 in complex with Aplysia californica acetylcholine binding protein (Ac-AChBP) at resolution of 2.6 & ANGS;, respectively. Based on the structure of the complexes, together with molecular dynamic simulation (MD-simulation), we suggested the key residues of alpha 9 alpha 10 nAChR in determining its high affinity for RgIA/RgIA4. This is the first time the complex between pain-related conotoxins and Ac-AChBP was reported and the complementary side of alpha 9 subunit in binding of the antagonists shown. These results provide realistic template for the design of new therapeutic in neuropathic pain.

Automated summary

The study elucidates the critical role of alpha 9-containing nicotinic acetylcholine receptors in neuropathic pain and reveals the key residues of alpha 9 alpha 10 nAChR that determine their high affinity for RgIA/RgIA4 through co-crystal structure and molecular dynamic simulations. This provides valuable insights for designing new therapeutic approaches for neuropathic pain.