Antagonistic Mechanism of α-Conotoxin BuIA toward the Human α3β2 Nicotinic Acetylcholine Receptor
| Autor: | Yanyan Chu, Tao Jiang, Rilei Yu, Huijie Liu, Ningning Wei, Qingliang Xu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Physiology
Cognitive Neuroscience Mutagenesis Molecular Conformation Nicotinic Antagonists Cell Biology General Medicine Receptors Nicotinic complex mixtures Biochemistry Acetylcholine Cell biology Transmembrane domain Nicotinic acetylcholine receptor chemistry.chemical_compound Nicotinic agonist nervous system chemistry Mutagenesis Site-Directed Humans Homology modeling Conotoxins Neurotransmitter Ion channel Acetylcholine receptor |
| Zdroj: | ACS Chemical Neuroscience. 12:4535-4545 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.1c00568 |
| Popis: | Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that are abundantly expressed in the central and peripheral nervous systems, playing an important role in mediating neurotransmitter release and inter-synaptic signaling. Dysfunctional nAChRs are associated with neurological disorders, and studying the structure and function of nAChRs is essential for development of drugs or strategies for treatment of related diseases. α-Conotoxins are selective antagonists of the nAChR and are an important class of drug leads. So far, the antagonistic mechanism of α-conotoxins toward the nAChRs is still unclear. In this study, we built an α3β2 nAChR homology model and investigated its conformational transition mechanism upon binding with a highly potent inhibitor, α-conotoxin BuIA, through μs molecular dynamic simulations and site-directed mutagenesis studies. The results suggested that the α3β2 nAChR underwent global conformational transitions and was stabilized into a closed state with three hydrophobic gates present in the transmembrane domain by BuIA. Finally, the probable antagonistic mechanism of BuIA was proposed. Overall, the closed-state model of the α3β2 nAChR bound with BuIA is not only essential for understanding the antagonistic mechanism of α-conotoxins but also particularly valuable for development of therapeutic inhibitors in future. |
| Databáze: | OpenAIRE |
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