From crystal structure of ?-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for ?3?2 nAChR.

ABSTRACT: Acetylcholine binding proteins (AChBPs) are unique spatial homologs of the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), and they reproduce some pharmacological properties of nAChRs. X-ray crystal structures of A?hBP in complex with ?-conotoxins provide important insights into the interactions of ?-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why ?-conotoxin GIC is strongly selective for ?3?2 nAChR, this question has not yet been solved. Here we present the structure of ?-conotoxin GIC in complex with Aplysia californica AChBP (Ac-AChBP) at a resolution of 2.1?Å. Based on this co-crystal structure complemented with molecular docking data, we suggest the key residues of GIC in determining its high affinity and selectivity for human ?3?2 vs ?3?4 nAChRs. These suggestions were checked by radioligand and electrophysiology experiments, which confirmed the functional role of detected contacts for GIC interactions with Ac-AChBP and ?3?2 nAChR subtypes. While GIC elements responsible for its high affinity binding with Ac-AChBP and ?3?2 nAChR were identified, our study also showed the limitations of computer modelling in extending the data from the X-ray structures of the AChBP complexes to all nAChR subtypes.

SUBMITTER: Lin B 

PROVIDER: S-EPMC4772116 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature