The crystal structure of Ac-AChBP in complex with ?-conotoxin LvIA reveals the mechanism of its selectivity towards different nAChR subtypes.

ABSTRACT: The ?3* nAChRs, which are considered to be promising drug targets for problems such as pain, addiction, cardiovascular function, cognitive disorders etc., are found throughout the central and peripheral nervous system. The ?-conotoxin (?-CTx) LvIA has been identified as the most selective inhibitor of ?3?2 nAChRs known to date, and it can distinguish the ?3?2 nAChR subtype from the ?6/?3?2?3 and ?3?4 nAChR subtypes. However, the mechanism of its selectivity towards ?3?2, ?6/?3?2?3, and ?3?4 nAChRs remains elusive. Here we report the co-crystal structure of LvIA in complex with Aplysia californica acetylcholine binding protein (Ac-AChBP) at a resolution of 3.4 Å. Based on the structure of this complex, together with homology modeling based on other nAChR subtypes and binding affinity assays, we conclude that Asp-11 of LvIA plays an important role in the selectivity of LvIA towards ?3?2 and ?3/?6?2?3 nAChRs by making a salt bridge with Lys-155 of the rat ?3 subunit. Asn-9 lies within a hydrophobic pocket that is formed by Met-36, Thr-59, and Phe-119 of the rat ?2 subunit in the ?3?2 nAChR model, revealing the reason for its more potent selectivity towards the ?3?2 nAChR subtype. These results provide molecular insights that can be used to design ligands that selectively target ?3?2 nAChRs, with significant implications for the design of new therapeutic ?-CTxs.

SUBMITTER: Xu M 

PROVIDER: S-EPMC5563285 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature