Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1
Transient receptor potential ankyrin 1 (TRPA1) is a transmembrane protein channeling the influx of calcium ions. As a polymodal nocisensor, TRPA1 can be activated by thermal, mechanical stimuli and a wide range of chemically damaging molecules including small volatile environmental toxicants and end...
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MDPI AG
2021-09-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/10/988 |
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| author | Balázs Zoltán Zsidó Rita Börzsei Erika Pintér Csaba Hetényi |
| author_facet | Balázs Zoltán Zsidó Rita Börzsei Erika Pintér Csaba Hetényi |
| author_sort | Balázs Zoltán Zsidó |
| collection | DOAJ |
| description | Transient receptor potential ankyrin 1 (TRPA1) is a transmembrane protein channeling the influx of calcium ions. As a polymodal nocisensor, TRPA1 can be activated by thermal, mechanical stimuli and a wide range of chemically damaging molecules including small volatile environmental toxicants and endogenous algogenic lipids. After activation by such compounds, the ion channel opens up, its central pore widens allowing calcium influx into the cytosol inducing signal transduction pathways. Afterwards, the calcium influx desensitizes irritant evoked responses and results in an inactive state of the ion channel. Recent experimental determination of structures of apo and holo forms of TRPA1 opened the way towards the design of new agonists, which can activate the ion channel. The present study is aimed at the elucidation of binding dynamics of agonists using experimental structures of TRPA1-agonist complexes at the atomic level applying molecular docking and dynamics methods accounting for covalent and non-covalent interactions. Following a test of docking methods focused on the final, holo structures, prerequisite binding modes were detected involving the apo forms. It was shown how reversible interactions with prerequisite binding sites contribute to structural changes of TRPA1 leading to covalent bonding of agonists. The proposed dynamics of action allowed a mechanism-based forecast of new, druggable binding sites of potent agonists. |
| first_indexed | 2024-03-10T06:17:43Z |
| format | Article |
| id | doaj.art-ebccfa188a3a492cab36dd5f5978853a |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T06:17:43Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj.art-ebccfa188a3a492cab36dd5f5978853a2023-11-22T19:35:38ZengMDPI AGPharmaceuticals1424-82472021-09-01141098810.3390/ph14100988Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1Balázs Zoltán Zsidó0Rita Börzsei1Erika Pintér2Csaba Hetényi3Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, HungaryDepartment of Pharmacology, Faculty of Pharmacy, University of Pécs, Szigeti út 12, 7624 Pécs, HungaryDepartment of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, HungaryDepartment of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, HungaryTransient receptor potential ankyrin 1 (TRPA1) is a transmembrane protein channeling the influx of calcium ions. As a polymodal nocisensor, TRPA1 can be activated by thermal, mechanical stimuli and a wide range of chemically damaging molecules including small volatile environmental toxicants and endogenous algogenic lipids. After activation by such compounds, the ion channel opens up, its central pore widens allowing calcium influx into the cytosol inducing signal transduction pathways. Afterwards, the calcium influx desensitizes irritant evoked responses and results in an inactive state of the ion channel. Recent experimental determination of structures of apo and holo forms of TRPA1 opened the way towards the design of new agonists, which can activate the ion channel. The present study is aimed at the elucidation of binding dynamics of agonists using experimental structures of TRPA1-agonist complexes at the atomic level applying molecular docking and dynamics methods accounting for covalent and non-covalent interactions. Following a test of docking methods focused on the final, holo structures, prerequisite binding modes were detected involving the apo forms. It was shown how reversible interactions with prerequisite binding sites contribute to structural changes of TRPA1 leading to covalent bonding of agonists. The proposed dynamics of action allowed a mechanism-based forecast of new, druggable binding sites of potent agonists.https://www.mdpi.com/1424-8247/14/10/988TRPA1 receptorprerequisite bindingcovalent binding |
| spellingShingle | Balázs Zoltán Zsidó Rita Börzsei Erika Pintér Csaba Hetényi Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1 Pharmaceuticals TRPA1 receptor prerequisite binding covalent binding |
| title | Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1 |
| title_full | Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1 |
| title_fullStr | Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1 |
| title_full_unstemmed | Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1 |
| title_short | Prerequisite Binding Modes Determine the Dynamics of Action of Covalent Agonists of Ion Channel TRPA1 |
| title_sort | prerequisite binding modes determine the dynamics of action of covalent agonists of ion channel trpa1 |
| topic | TRPA1 receptor prerequisite binding covalent binding |
| url | https://www.mdpi.com/1424-8247/14/10/988 |
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