Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739
| Autor: | Elnaz Aledavood, Aria Gheeraert, Alessia Forte, Laurent Vuillon, Ivan Rivalta, F. Javier Luque, Carolina Estarellas |
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| Přispěvatelé: | Aledavood E., Gheeraert A., Forte A., Vuillon L., Rivalta I., Luque F.J., Estarellas C. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Gene isoform
AMPK pan-activator QH301-705.5 Molecular dynamics Biochemistry Genetics and Molecular Biology (miscellaneous) Biochemistry Heterotrimeric G protein medicine Cinètica enzimàtica Molecular Biosciences Dinàmica molecular Biology (General) Protein kinase A Molecular Biology Original Research Activator (genetics) Mechanism (biology) Chemistry Enzyme kinetics Adenosine protein activation mechanism Enzymes Cell biology Cell metabolism molecular dynamics simulation protein dynamic Enzims medicine.drug isoform selectivity |
| Zdroj: | Frontiers in Molecular Biosciences, Vol 8 (2021) Frontiers in Molecular Biosciences Dipòsit Digital de la UB Universidad de Barcelona |
| DOI: | 10.3389/fmolb.2021.760026/full |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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