Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.

Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/threonine protein kinases. It is a key regulator downstream of various growth factors and hormones and is involved in malignant transformation and chemo-resistance. Full-length PKB protein has not been crystallised, thus stu...

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Autores principales:	Véronique Calleja, Michel Laguerre, Peter J Parker, Banafshé Larijani
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3ce069f4945b40748f528311683fff7a
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spelling	oai:doaj.org-article:3ce069f4945b40748f528311683fff7a2021-11-25T05:33:50ZRole of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.1544-91731545-788510.1371/journal.pbio.1000017https://doaj.org/article/3ce069f4945b40748f528311683fff7a2009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19166270/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/threonine protein kinases. It is a key regulator downstream of various growth factors and hormones and is involved in malignant transformation and chemo-resistance. Full-length PKB protein has not been crystallised, thus studying the molecular mechanisms that are involved in its regulation in relation to its structure have not been simple. Recently, the dynamics between the inactive and active conformer at the molecular level have been described. The maintenance of PKB's inactive state via the interaction of the PH and kinase domains prevents its activation loop to be phosphorylated by its upstream activator, phosphoinositide-dependent protein kinase-1 (PDK1). By using a multidisciplinary approach including molecular modelling, classical biochemical assays, and Förster resonance energy transfer (FRET)/two-photon fluorescence lifetime imaging microscopy (FLIM), a detailed model depicting the interaction between the different domains of PKB in its inactive conformation was demonstrated. These findings in turn clarified the molecular mechanism of PKB inhibition by AKT inhibitor VIII (a specific allosteric inhibitor) and illustrated at the molecular level its selectivity towards different PKB isoforms. Furthermore, these findings allude to the possible function of the C-terminus in sustaining the inactive conformer of PKB. This study presents essential insights into the quaternary structure of PKB in its inactive conformation. An understanding of PKB structure in relation to its function is critical for elucidating its mode of activation and discovering how to modulate its activity. The molecular mechanism of inhibition of PKB activation by the specific drug AKT inhibitor VIII has critical implications for determining the mechanism of inhibition of other allosteric inhibitors and for opening up opportunities for the design of new generations of modulator drugs.Véronique CallejaMichel LaguerrePeter J ParkerBanafshé LarijaniPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 7, Iss 1, p e17 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Véronique Calleja Michel Laguerre Peter J Parker Banafshé Larijani Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.
description	Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/threonine protein kinases. It is a key regulator downstream of various growth factors and hormones and is involved in malignant transformation and chemo-resistance. Full-length PKB protein has not been crystallised, thus studying the molecular mechanisms that are involved in its regulation in relation to its structure have not been simple. Recently, the dynamics between the inactive and active conformer at the molecular level have been described. The maintenance of PKB's inactive state via the interaction of the PH and kinase domains prevents its activation loop to be phosphorylated by its upstream activator, phosphoinositide-dependent protein kinase-1 (PDK1). By using a multidisciplinary approach including molecular modelling, classical biochemical assays, and Förster resonance energy transfer (FRET)/two-photon fluorescence lifetime imaging microscopy (FLIM), a detailed model depicting the interaction between the different domains of PKB in its inactive conformation was demonstrated. These findings in turn clarified the molecular mechanism of PKB inhibition by AKT inhibitor VIII (a specific allosteric inhibitor) and illustrated at the molecular level its selectivity towards different PKB isoforms. Furthermore, these findings allude to the possible function of the C-terminus in sustaining the inactive conformer of PKB. This study presents essential insights into the quaternary structure of PKB in its inactive conformation. An understanding of PKB structure in relation to its function is critical for elucidating its mode of activation and discovering how to modulate its activity. The molecular mechanism of inhibition of PKB activation by the specific drug AKT inhibitor VIII has critical implications for determining the mechanism of inhibition of other allosteric inhibitors and for opening up opportunities for the design of new generations of modulator drugs.
format	article
author	Véronique Calleja Michel Laguerre Peter J Parker Banafshé Larijani
author_facet	Véronique Calleja Michel Laguerre Peter J Parker Banafshé Larijani
author_sort	Véronique Calleja
title	Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.
title_short	Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.
title_full	Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.
title_fullStr	Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.
title_full_unstemmed	Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.
title_sort	role of a novel ph-kinase domain interface in pkb/akt regulation: structural mechanism for allosteric inhibition.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/3ce069f4945b40748f528311683fff7a
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_version_	1718414572626378752

Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.

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