Computational determination of the binding mode of α-conotoxin to nicotinic acetylcholine receptor

Tabassum, Nargis; Yu, Rilei; Jiang, Tao

doi:10.1007/s11802-016-3049-y

Cited by 2 publications

(3 citation statements)

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“…Moreover, the modes of binding of α-conotoxin ImI to our model of the closed-locked human α7 have been investigated. Here we focus our attention on the triad Asp5-Pro6-Arg7 on α-conotoxin ImI, experimentally known to be relevant in the interaction of this toxin with the α7 protein. ,− Pairwise interactions are described in literature between: (i) Asp5 and Arg7 in conotoxin, in concert with (ii) interaction of Arg7 with the side chain of Asp197 and the backbone oxygen of Pro196, in the primary subunit; (iii) between Arg7 in conotoxin and the side chain of Tyr93 in the primary subunit. These interactions have been evaluated by a hydrogen bond analysis between donor–acceptor pairs in the residues above listed.…”

Section: Methodsmentioning

confidence: 99%

Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study

Chiodo

Malliavin

Giuffrida

et al. 2018

J. Chem. Inf. Model.

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Journal of Chemical Information and Modeling gated ion channels (LGICs), are membrane proteins present in neurons and at neuromuscular junctions. They are responsible for signal transmission, and their function is regulated by neurotransmitters, agonists and antagonists drugs. A detailed knowledge of their conformational transition in response to ligand binding is critical to understand the basis of ligand-receptor interaction, in view of new pharmacological approaches to control receptor activity. However, the scarcity of experimentally derived structures of human channels makes this perspective extremely challenging. To contribute overcoming this issue, we have recently reported structural models for the open and the desensitized states of the human α7 nicotinic receptor. Here, we provide all-atom structural models of the same receptor in two different non-conductive states. The first structure, built via homology modeling and relaxed with extensive Molecular Dynamics simulations, represents the receptor bound to the natural antagonist α-conotoxin ImI. After comparison with available experimental data and computational models of other eukaryotic LGICs, we deem it consistent with the "closed-locked" state. The second model, obtained with simulations from the spontaneous relaxation of the open, agonist-bound α7 structure after ligand removal, recapitulates the characteristics of the apo-resting state of the receptor. These results add to our previous work on the active and desensitized state conformations, contributing to the structural characterization of the conformational landscape of the human α7 receptor, and suggesting benchmarks to discriminate among conformations found in experiments or in simulations of LGICs. In particular key interactions at the interface between the extracellular domain and the transmembrane domain are identified, that could be critical to the α7 receptor function.

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Section: Methodsmentioning

confidence: 99%

Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study

Chiodo

Malliavin

Giuffrida

et al. 2018

J. Chem. Inf. Model.

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“…These structures have served as templates for homology modelling of nAChR due to the high sequence similarity between AChBP and the ECD of nAChRs (Sine and Engel, 2006). MD simulations have been used to refine the structures and examine the motions of many α-CTX/nAChR complexes built by homology modelling, and these studies have been extensively surveyed elsewhere (Dutertre and Lewis, 2004;Tabassum et al, 2016). In a recent study, a homology model of α-conotoxin GIC bound to α3β2 nAChR was generated but could not be used to explain all mutational data (Lin et al, 2016).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Molecular model of the interaction between conotoxins and nAChRs provided qualitative insight of important pairwise interactions, but the low resolution of such models prevented the quantitative predictions of absolute binding affinities, for example using umbrella sampling. Nevertheless, several studies have used mutational energy prediction to support the validity of computational models (Tabassum et al, 2016). For example, Yu and colleagues used a combination of molecular mechanics (MM) simulations and Poisson-Boltzmann/Surface Area (PBSA) free energy (∆G) calculations to estimate the mutational free energies of a range of ImI mutants bound to the homopentameric α7 nAChR (Yu et al, 2011).…”

Section: Accepted Manuscriptmentioning

confidence: 99%