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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Elnaz Aledavood, Aria Gheeraert, Alessia Forte, Laurent Vuillon, Ivan Rivalta, F. Javier Luque, Carolina Estarellas
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	AMPK protein dynamic protein activation mechanism pan-activator isoform selectivity molecular dynamics simulation Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/88ab5e8ff89d4ee7b3e4f0385d933a5a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:88ab5e8ff89d4ee7b3e4f0385d933a5a
record_format	dspace
spelling	oai:doaj.org-article:88ab5e8ff89d4ee7b3e4f0385d933a5a2021-11-05T06:45:03ZElucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-7392296-889X10.3389/fmolb.2021.760026https://doaj.org/article/88ab5e8ff89d4ee7b3e4f0385d933a5a2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmolb.2021.760026/fullhttps://doaj.org/toc/2296-889XAdenosine 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.Elnaz AledavoodAria GheeraertAria GheeraertAlessia ForteLaurent VuillonIvan RivaltaIvan RivaltaF. Javier LuqueF. Javier LuqueCarolina EstarellasFrontiers Media S.A.articleAMPKprotein dynamicprotein activation mechanismpan-activatorisoform selectivitymolecular dynamics simulationBiology (General)QH301-705.5ENFrontiers in Molecular Biosciences, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	AMPK protein dynamic protein activation mechanism pan-activator isoform selectivity molecular dynamics simulation Biology (General) QH301-705.5
spellingShingle	AMPK protein dynamic protein activation mechanism pan-activator isoform selectivity molecular dynamics simulation Biology (General) QH301-705.5 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
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.
format	article
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
title	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_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_sort	elucidating the activation mechanism of ampk by direct pan-activator pf-739
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/88ab5e8ff89d4ee7b3e4f0385d933a5a
work_keys_str_mv	AT elnazaledavood elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739 AT ariagheeraert elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739 AT ariagheeraert elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739 AT alessiaforte elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739 AT laurentvuillon elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739 AT ivanrivalta elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739 AT ivanrivalta elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739 AT fjavierluque elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739 AT fjavierluque elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739 AT carolinaestarellas elucidatingtheactivationmechanismofampkbydirectpanactivatorpf739
_version_	1718444480902725632

Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739

Ejemplares similares