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 AСhBP in complex with α-conotoxins provide important insights into the interactions of α-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why α-conotoxin GIC is strongly selective for α3β2 nAChR, this question has not yet been solved. Here we present the structure of α-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 α3β2 vs α3β4 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 α3β2 nAChR subtypes. While GIC elements responsible for its high affinity binding with Ac-AChBP and α3β2 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.
Highlights
We present the co-crystal structure at a resolution of 2.1 Å of the α -conotoxin GIC in complex with Ac-acetylcholine-binding protein (AChBP) as a further step to shed light on the selectivity mechanisms in nicotinic acetylcholine receptors (nAChR) research
All Ac-AChBP/α -conotoxin co-crystal structures are similar, but the residues interacting at the binding sites are different (Supplementary Table 2)
Different α -conotoxins exhibit a wide range in selectivity towards distinct nAChR subtypes, reflected in different pharmacological properties (Supplementary Table 3)
Summary
Aplysia californica (Ac-AChBP) (see recent reviews[6,7,8,9,10]). These two proteins have remarkable differences in their affinity both to α -neurotoxins and different α -conotoxins and this is one of the factors that makes a step from the high-resolution X-ray structure of the AChBP complexes to the expected structures of the distinct nAChRs binding the same ligands more difficult. We analysed the α -conotoxin GIC bound to the neuronal α 3β 2 nAChR These receptors are present in the human brain, are involved in functions such as cognition and, among other neuronal nAChRs, are considered to be promising drug targets (see reviews). Α -Conotoxin GIC from Conus geographus venom is an extremely interesting peptide that potently and selectively blocks neuronal α 3β 2 nAChRs at very low concentrations (IC50 1.1 nM). This high selectivity for the human neuronal α 3β 2 receptor makes it one of the most attractive cholinergic ligands found in recent years. We present the co-crystal structure at a resolution of 2.1 Å of the α -conotoxin GIC in complex with Ac-AChBP as a further step to shed light on the selectivity mechanisms in nAChRs research
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