Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739
Adenosine monophosphate-activated protein kinase (AMPK) is a key energy sensor regulating the cell metabolism in response to energy supply and demand. The evolutionary adaptation of AMPK to different tissues is accomplished through the expression of distinct isoforms that can form up to 12 heterotri...
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| Format: | Article |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2021.760026/full |
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| author | Elnaz Aledavood Aria Gheeraert Aria Gheeraert Alessia Forte Laurent Vuillon Ivan Rivalta Ivan Rivalta F. Javier Luque F. Javier Luque Carolina Estarellas |
| author_facet | Elnaz Aledavood Aria Gheeraert Aria Gheeraert Alessia Forte Laurent Vuillon Ivan Rivalta Ivan Rivalta F. Javier Luque F. Javier Luque Carolina Estarellas |
| author_sort | Elnaz Aledavood |
| collection | DOAJ |
| description | Adenosine monophosphate-activated protein kinase (AMPK) is a key energy sensor regulating the cell metabolism in response to energy supply and demand. The evolutionary adaptation of AMPK to different tissues is accomplished through the expression of distinct isoforms that can form up to 12 heterotrimeric complexes, which exhibit notable differences in the sensitivity to direct activators. To comprehend the molecular factors of the activation mechanism of AMPK, we have assessed the changes in the structural and dynamical properties of β1- and β2-containing AMPK complexes formed upon binding to the pan-activator PF-739. The analysis revealed the molecular basis of the PF-739-mediated activation of AMPK and enabled us to identify distinctive features that may justify the slightly higher affinity towards the β1−isoform, such as the β1−Asn111 to β2−Asp111 substitution, which seems to be critical for modulating the dynamical sensitivity of β1- and β2 isoforms. The results are valuable in the design of selective activators to improve the tissue specificity of therapeutic treatment. |
| first_indexed | 2024-12-20T04:37:36Z |
| format | Article |
| id | doaj.art-88ab5e8ff89d4ee7b3e4f0385d933a5a |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-20T04:37:36Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-88ab5e8ff89d4ee7b3e4f0385d933a5a2022-12-21T19:53:12ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2021-11-01810.3389/fmolb.2021.760026760026Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739Elnaz Aledavood0Aria Gheeraert1Aria Gheeraert2Alessia Forte3Laurent Vuillon4Ivan Rivalta5Ivan Rivalta6F. Javier Luque7F. Javier Luque8Carolina Estarellas9Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, and Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, Barcelona, SpainDipartimento di Chimica Industriale “Toso Montanari” Università di Bologna, Bologna, ItalyLAMA, University of Savoie Mont Blanc, CNRS, LAMA, Le Bourget du Lac, FranceDepartment of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, and Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, Barcelona, SpainLAMA, University of Savoie Mont Blanc, CNRS, LAMA, Le Bourget du Lac, FranceDipartimento di Chimica Industriale “Toso Montanari” Università di Bologna, Bologna, ItalyUniversité de Lyon, École Normale Supérieure de Lyon, CNRS UMR 5182, Laboratoire de Chimie, Lyon, FranceDepartment of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, and Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, Barcelona, SpainInstitute of Biomedicine (IBUB), University of Barcelona, Barcelona, SpainDepartment of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, and Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, Barcelona, SpainAdenosine monophosphate-activated protein kinase (AMPK) is a key energy sensor regulating the cell metabolism in response to energy supply and demand. The evolutionary adaptation of AMPK to different tissues is accomplished through the expression of distinct isoforms that can form up to 12 heterotrimeric complexes, which exhibit notable differences in the sensitivity to direct activators. To comprehend the molecular factors of the activation mechanism of AMPK, we have assessed the changes in the structural and dynamical properties of β1- and β2-containing AMPK complexes formed upon binding to the pan-activator PF-739. The analysis revealed the molecular basis of the PF-739-mediated activation of AMPK and enabled us to identify distinctive features that may justify the slightly higher affinity towards the β1−isoform, such as the β1−Asn111 to β2−Asp111 substitution, which seems to be critical for modulating the dynamical sensitivity of β1- and β2 isoforms. The results are valuable in the design of selective activators to improve the tissue specificity of therapeutic treatment.https://www.frontiersin.org/articles/10.3389/fmolb.2021.760026/fullAMPKprotein dynamicprotein activation mechanismpan-activatorisoform selectivitymolecular dynamics simulation |
| spellingShingle | Elnaz Aledavood Aria Gheeraert Aria Gheeraert Alessia Forte Laurent Vuillon Ivan Rivalta Ivan Rivalta F. Javier Luque F. Javier Luque Carolina Estarellas Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739 Frontiers in Molecular Biosciences AMPK protein dynamic protein activation mechanism pan-activator isoform selectivity molecular dynamics simulation |
| title | Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739 |
| title_full | Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739 |
| title_fullStr | Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739 |
| title_full_unstemmed | Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739 |
| title_short | Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739 |
| title_sort | elucidating the activation mechanism of ampk by direct pan activator pf 739 |
| topic | AMPK protein dynamic protein activation mechanism pan-activator isoform selectivity molecular dynamics simulation |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2021.760026/full |
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