Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine Receptor
The α4β2 nAChR is implicated in a range of diseases and disorders including nicotine addiction, epilepsy and Parkinson’s and Alzheimer’s diseases. Designing α4β2 nAChR selective inhibitors could help define the role of the α4β2 nAChR in such disease states. In this study, we aimed to modify globular...
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| Format: | Article |
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MDPI AG
2021-08-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/19/9/482 |
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| author | Xiaosa Wu David J. Craik Quentin Kaas |
| author_facet | Xiaosa Wu David J. Craik Quentin Kaas |
| author_sort | Xiaosa Wu |
| collection | DOAJ |
| description | The α4β2 nAChR is implicated in a range of diseases and disorders including nicotine addiction, epilepsy and Parkinson’s and Alzheimer’s diseases. Designing α4β2 nAChR selective inhibitors could help define the role of the α4β2 nAChR in such disease states. In this study, we aimed to modify globular and ribbon α-conotoxin GID to selectively target the α4β2 nAChR through competitive inhibition of the α4(+)β2(−) or α4(+)α4(−) interfaces. The binding modes of the globular α-conotoxin [γ4E]GID with rat α3β2, α4β2 and α7 nAChRs were deduced using computational methods and were validated using published experimental data. The binding mode of globular [γ4E]GID at α4β2 nAChR can explain the experimental mutagenesis data, suggesting that it could be used to design GID variants. The predicted mutational energy results showed that globular [γ4E]GID is optimal for binding to α4β2 nAChR and its activity could not likely be further improved through amino-acid substitutions. The binding mode of ribbon GID with the (α4)<sub>3</sub>(β2)<sub>2</sub> nAChR was deduced using the information from the cryo-electron structure of (α4)<sub>3</sub>(β2)<sub>2</sub> nAChR and the binding mode of ribbon AuIB. The program FoldX predicted the mutational energies of ribbon [γ4E]GID at the α4(+)α4(−) interface, and several ribbon[γ4E]GID mutants were suggested to have desirable properties to inhibit (α4)<sub>3</sub>(β2)<sub>2</sub> nAChR. |
| first_indexed | 2024-03-10T07:29:56Z |
| format | Article |
| id | doaj.art-5fcb53a97c2f4c5c80ad2a6663dea515 |
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| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-10T07:29:56Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-5fcb53a97c2f4c5c80ad2a6663dea5152023-11-22T13:58:27ZengMDPI AGMarine Drugs1660-33972021-08-0119948210.3390/md19090482Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine ReceptorXiaosa Wu0David J. Craik1Quentin Kaas2Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, AustraliaInstitute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, AustraliaInstitute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, AustraliaThe α4β2 nAChR is implicated in a range of diseases and disorders including nicotine addiction, epilepsy and Parkinson’s and Alzheimer’s diseases. Designing α4β2 nAChR selective inhibitors could help define the role of the α4β2 nAChR in such disease states. In this study, we aimed to modify globular and ribbon α-conotoxin GID to selectively target the α4β2 nAChR through competitive inhibition of the α4(+)β2(−) or α4(+)α4(−) interfaces. The binding modes of the globular α-conotoxin [γ4E]GID with rat α3β2, α4β2 and α7 nAChRs were deduced using computational methods and were validated using published experimental data. The binding mode of globular [γ4E]GID at α4β2 nAChR can explain the experimental mutagenesis data, suggesting that it could be used to design GID variants. The predicted mutational energy results showed that globular [γ4E]GID is optimal for binding to α4β2 nAChR and its activity could not likely be further improved through amino-acid substitutions. The binding mode of ribbon GID with the (α4)<sub>3</sub>(β2)<sub>2</sub> nAChR was deduced using the information from the cryo-electron structure of (α4)<sub>3</sub>(β2)<sub>2</sub> nAChR and the binding mode of ribbon AuIB. The program FoldX predicted the mutational energies of ribbon [γ4E]GID at the α4(+)α4(−) interface, and several ribbon[γ4E]GID mutants were suggested to have desirable properties to inhibit (α4)<sub>3</sub>(β2)<sub>2</sub> nAChR.https://www.mdpi.com/1660-3397/19/9/482α4β2 nAChRα-conotoxinmolecular dynamics simulationFoldXdrug design |
| spellingShingle | Xiaosa Wu David J. Craik Quentin Kaas Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine Receptor Marine Drugs α4β2 nAChR α-conotoxin molecular dynamics simulation FoldX drug design |
| title | Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine Receptor |
| title_full | Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine Receptor |
| title_fullStr | Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine Receptor |
| title_full_unstemmed | Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine Receptor |
| title_short | Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine Receptor |
| title_sort | interactions of globular and ribbon γ4e gid with α4β2 neuronal nicotinic acetylcholine receptor |
| topic | α4β2 nAChR α-conotoxin molecular dynamics simulation FoldX drug design |
| url | https://www.mdpi.com/1660-3397/19/9/482 |
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