دورية أكاديمية
Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations.
| العنوان: | Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations. |
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| المؤلفون: | Mosa FES; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada., AlRawashdeh S; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada., El-Kadi AOS; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada., Barakat K; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada. |
| المصدر: | Journal of chemical information and modeling [J Chem Inf Model] 2024 Mar 25; Vol. 64 (6), pp. 2021-2034. Date of Electronic Publication: 2024 Mar 08. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101230060 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-960X (Electronic) Linking ISSN: 15499596 NLM ISO Abbreviation: J Chem Inf Model Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society, c2005- |
| مواضيع طبية MeSH: | Receptors, Aryl Hydrocarbon*/metabolism , Artificial Intelligence*, Humans ; Ligands ; Aryl Hydrocarbon Receptor Nuclear Translocator/chemistry ; Aryl Hydrocarbon Receptor Nuclear Translocator/genetics ; Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism |
| مستخلص: | The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates biological signals to control various complicated cellular functions. It plays a crucial role in environmental sensing and xenobiotic metabolism. Dysregulation of AhR is associated with health concerns, including cancer and immune system disorders. Upon binding to AhR ligands, AhR, along with heat shock protein 90 and other partner proteins undergoes a transformation in the nucleus, heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT), and mediates numerous biological functions by inducing the transcription of various AhR-responsive genes. In this manuscript, the 3-dimensional structure of the entire human AhR is obtained using an artificial intelligence tool, and molecular dynamics (MD) simulations are performed to study different structural conformations. These conformations provide insights into the protein's function and movement in response to ligand binding. Understanding the dynamic behavior of AhR will contribute to the development of targeted therapies for associated health conditions. Therefore, we employ well-tempered metadynamics (WTE-metaD) simulations to explore the conformational landscape of AhR and obtain a better understanding of its functional behavior. Our computational results are in excellent agreement with previous experimental findings, revealing the closed and open states of helix α1 in the basic helix-loop-helix (bHLH domain) in the cytoplasm at the atomic level. We also predict the inactive form of AhR and identify Arginine 42 as a key residue that regulates switching between closed and open conformations in existing AhR modulators. |
| المشرفين على المادة: | 0 (Receptors, Aryl Hydrocarbon) 0 (Ligands) 138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator) |
| تواريخ الأحداث: | Date Created: 20240308 Date Completed: 20240326 Latest Revision: 20240806 |
| رمز التحديث: | 20240806 |
| DOI: | 10.1021/acs.jcim.4c00169 |
| PMID: | 38457778 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1549-960X |
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| DOI: | 10.1021/acs.jcim.4c00169 |