Allosteric activation of the protein kinase PDK1 with low molecular weight compounds
Identifieur interne : 002A32 ( Main/Exploration ); précédent : 002A31; suivant : 002A33Allosteric activation of the protein kinase PDK1 with low molecular weight compounds
Auteurs : Matthias Engel [Allemagne] ; Valerie Hindie [Allemagne, France] ; Laura A. Lopez-Garcia [Allemagne] ; Adriana Stroba [Allemagne] ; Francis Schaeffer [France] ; Iris Adrian [Allemagne] ; Jochen Imig [Allemagne] ; Leila Idrissova [Allemagne] ; Wolfgang Nastainczyk [Allemagne] ; Stefan Zeuzem [Allemagne] ; Pedro M. Alzari [France] ; Rolf W. Hartmann [Allemagne] ; Albrecht Piiper [Allemagne] ; Ricardo M. Biondi [Allemagne]Source :
- The EMBO Journal [ 0261-4189 ] ; 2006-11-29.
Abstract
Organisms rely heavily on protein phosphorylation to transduce intracellular signals. The phosphorylation of a protein often induces conformational changes, which are responsible for triggering downstream cellular events. Protein kinases are themselves frequently regulated by phosphorylation. Recently, we and others proposed the molecular mechanism by which phosphorylation at a hydrophobic motif (HM) regulates the conformation and activity of many members of the AGC group of protein kinases. Here we have developed specific, low molecular weight compounds, which target the HM/PIF‐pocket and have the ability to allosterically activate phosphoinositide‐dependent protein kinase 1 (PDK1) by modulating the phosphorylation‐dependent conformational transition. The mechanism of action of these compounds was characterized by mutagenesis of PDK1, synthesis of compound analogs, interaction‐displacement studies and isothermal titration calorimetry experiments. Our results raise the possibility of developing drugs that target the AGC kinases via a novel mode of action and may inspire future rational development of compounds with the ability to modulate phosphorylation‐dependent conformational transitions in other proteins.
Url:
DOI: 10.1038/sj.emboj.7601416
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream Istex, to step Corpus: 001445
- to stream Istex, to step Curation: 001443
- to stream Istex, to step Checkpoint: 000A44
- to stream Main, to step Merge: 002D52
- to stream Main, to step Curation: 002A32
Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Allosteric activation of the protein kinase PDK1 with low molecular weight compounds</title><author><name sortKey="Engel, Matthias" sort="Engel, Matthias" uniqKey="Engel M" first="Matthias" last="Engel">Matthias Engel</name></author><author><name sortKey="Hindie, Valerie" sort="Hindie, Valerie" uniqKey="Hindie V" first="Valerie" last="Hindie">Valerie Hindie</name></author><author><name sortKey="Lopez Arcia, Laura A" sort="Lopez Arcia, Laura A" uniqKey="Lopez Arcia L" first="Laura A" last="Lopez-Garcia">Laura A. Lopez-Garcia</name></author><author><name sortKey="Stroba, Adriana" sort="Stroba, Adriana" uniqKey="Stroba A" first="Adriana" last="Stroba">Adriana Stroba</name></author><author><name sortKey="Schaeffer, Francis" sort="Schaeffer, Francis" uniqKey="Schaeffer F" first="Francis" last="Schaeffer">Francis Schaeffer</name></author><author><name sortKey="Adrian, Iris" sort="Adrian, Iris" uniqKey="Adrian I" first="Iris" last="Adrian">Iris Adrian</name></author><author><name sortKey="Imig, Jochen" sort="Imig, Jochen" uniqKey="Imig J" first="Jochen" last="Imig">Jochen Imig</name></author><author><name sortKey="Idrissova, Leila" sort="Idrissova, Leila" uniqKey="Idrissova L" first="Leila" last="Idrissova">Leila Idrissova</name></author><author><name sortKey="Nastainczyk, Wolfgang" sort="Nastainczyk, Wolfgang" uniqKey="Nastainczyk W" first="Wolfgang" last="Nastainczyk">Wolfgang Nastainczyk</name></author><author><name sortKey="Zeuzem, Stefan" sort="Zeuzem, Stefan" uniqKey="Zeuzem S" first="Stefan" last="Zeuzem">Stefan Zeuzem</name></author><author><name sortKey="Alzari, Pedro M" sort="Alzari, Pedro M" uniqKey="Alzari P" first="Pedro M" last="Alzari">Pedro M. Alzari</name></author><author><name sortKey="Hartmann, Rolf W" sort="Hartmann, Rolf W" uniqKey="Hartmann R" first="Rolf W" last="Hartmann">Rolf W. Hartmann</name></author><author><name sortKey="Piiper, Albrecht" sort="Piiper, Albrecht" uniqKey="Piiper A" first="Albrecht" last="Piiper">Albrecht Piiper</name></author><author><name sortKey="Biondi, Ricardo M" sort="Biondi, Ricardo M" uniqKey="Biondi R" first="Ricardo M" last="Biondi">Ricardo M. Biondi</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:8BF57A0158BD8FD4B2E43B4F90225E7A49D8E459</idno><date when="2006" year="2006">2006</date><idno type="doi">10.1038/sj.emboj.7601416</idno><idno type="url">https://api.istex.fr/document/8BF57A0158BD8FD4B2E43B4F90225E7A49D8E459/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001445</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001445</idno><idno type="wicri:Area/Istex/Curation">001443</idno><idno type="wicri:Area/Istex/Checkpoint">000A44</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000A44</idno><idno type="wicri:doubleKey">0261-4189:2006:Engel M:allosteric:activation:of</idno><idno type="wicri:Area/Main/Merge">002D52</idno><idno type="wicri:Area/Main/Curation">002A32</idno><idno type="wicri:Area/Main/Exploration">002A32</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Allosteric activation of the protein kinase PDK1 with low molecular weight compounds</title><author><name sortKey="Engel, Matthias" sort="Engel, Matthias" uniqKey="Engel M" first="Matthias" last="Engel">Matthias Engel</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Pharmaceutical and Medicinal Chemistry, University of Saarland, Saarbrücken</wicri:regionArea><placeName><region type="land" nuts="2">Sarre (Land)</region><settlement type="city">Sarrebruck</settlement></placeName></affiliation></author><author><name sortKey="Hindie, Valerie" sort="Hindie, Valerie" uniqKey="Hindie V" first="Valerie" last="Hindie">Valerie Hindie</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg</wicri:regionArea><wicri:noRegion>Homburg</wicri:noRegion><wicri:noRegion>Homburg</wicri:noRegion></affiliation><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Structural Biochemistry Unit, Pasteur Institute, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Lopez Arcia, Laura A" sort="Lopez Arcia, Laura A" uniqKey="Lopez Arcia L" first="Laura A" last="Lopez-Garcia">Laura A. Lopez-Garcia</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg</wicri:regionArea><wicri:noRegion>Homburg</wicri:noRegion><wicri:noRegion>Homburg</wicri:noRegion></affiliation></author><author><name sortKey="Stroba, Adriana" sort="Stroba, Adriana" uniqKey="Stroba A" first="Adriana" last="Stroba">Adriana Stroba</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Pharmaceutical and Medicinal Chemistry, University of Saarland, Saarbrücken</wicri:regionArea><placeName><region type="land" nuts="2">Sarre (Land)</region><settlement type="city">Sarrebruck</settlement></placeName></affiliation></author><author><name sortKey="Schaeffer, Francis" sort="Schaeffer, Francis" uniqKey="Schaeffer F" first="Francis" last="Schaeffer">Francis Schaeffer</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Structural Biochemistry Unit, Pasteur Institute, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Adrian, Iris" sort="Adrian, Iris" uniqKey="Adrian I" first="Iris" last="Adrian">Iris Adrian</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg</wicri:regionArea><wicri:noRegion>Homburg</wicri:noRegion><wicri:noRegion>Homburg</wicri:noRegion></affiliation></author><author><name sortKey="Imig, Jochen" sort="Imig, Jochen" uniqKey="Imig J" first="Jochen" last="Imig">Jochen Imig</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg</wicri:regionArea><wicri:noRegion>Homburg</wicri:noRegion><wicri:noRegion>Homburg</wicri:noRegion></affiliation></author><author><name sortKey="Idrissova, Leila" sort="Idrissova, Leila" uniqKey="Idrissova L" first="Leila" last="Idrissova">Leila Idrissova</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg</wicri:regionArea><wicri:noRegion>Homburg</wicri:noRegion><wicri:noRegion>Homburg</wicri:noRegion></affiliation></author><author><name sortKey="Nastainczyk, Wolfgang" sort="Nastainczyk, Wolfgang" uniqKey="Nastainczyk W" first="Wolfgang" last="Nastainczyk">Wolfgang Nastainczyk</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Medicinal Biochemistry, University of Saarland, Homburg</wicri:regionArea><wicri:noRegion>Homburg</wicri:noRegion><wicri:noRegion>Homburg</wicri:noRegion></affiliation></author><author><name sortKey="Zeuzem, Stefan" sort="Zeuzem, Stefan" uniqKey="Zeuzem S" first="Stefan" last="Zeuzem">Stefan Zeuzem</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg</wicri:regionArea><wicri:noRegion>Homburg</wicri:noRegion><wicri:noRegion>Homburg</wicri:noRegion></affiliation></author><author><name sortKey="Alzari, Pedro M" sort="Alzari, Pedro M" uniqKey="Alzari P" first="Pedro M" last="Alzari">Pedro M. Alzari</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Structural Biochemistry Unit, Pasteur Institute, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Hartmann, Rolf W" sort="Hartmann, Rolf W" uniqKey="Hartmann R" first="Rolf W" last="Hartmann">Rolf W. Hartmann</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Pharmaceutical and Medicinal Chemistry, University of Saarland, Saarbrücken</wicri:regionArea><placeName><region type="land" nuts="2">Sarre (Land)</region><settlement type="city">Sarrebruck</settlement></placeName></affiliation></author><author><name sortKey="Piiper, Albrecht" sort="Piiper, Albrecht" uniqKey="Piiper A" first="Albrecht" last="Piiper">Albrecht Piiper</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg</wicri:regionArea><wicri:noRegion>Homburg</wicri:noRegion><wicri:noRegion>Homburg</wicri:noRegion></affiliation></author><author><name sortKey="Biondi, Ricardo M" sort="Biondi, Ricardo M" uniqKey="Biondi R" first="Ricardo M" last="Biondi">Ricardo M. Biondi</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg</wicri:regionArea><wicri:noRegion>Homburg</wicri:noRegion><wicri:noRegion>Homburg</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Allemagne</country></affiliation></author></analytic><monogr></monogr><series><title level="j">The EMBO Journal</title><idno type="ISSN">0261-4189</idno><idno type="eISSN">1460-2075</idno><imprint><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2006-11-29">2006-11-29</date><biblScope unit="volume">25</biblScope><biblScope unit="issue">23</biblScope><biblScope unit="page" from="5469">5469</biblScope><biblScope unit="page" to="5480">5480</biblScope></imprint><idno type="ISSN">0261-4189</idno></series><idno type="istex">8BF57A0158BD8FD4B2E43B4F90225E7A49D8E459</idno><idno type="DOI">10.1038/sj.emboj.7601416</idno><idno type="ArticleID">EMBJ7601416</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0261-4189</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Organisms rely heavily on protein phosphorylation to transduce intracellular signals. The phosphorylation of a protein often induces conformational changes, which are responsible for triggering downstream cellular events. Protein kinases are themselves frequently regulated by phosphorylation. Recently, we and others proposed the molecular mechanism by which phosphorylation at a hydrophobic motif (HM) regulates the conformation and activity of many members of the AGC group of protein kinases. Here we have developed specific, low molecular weight compounds, which target the HM/PIF‐pocket and have the ability to allosterically activate phosphoinositide‐dependent protein kinase 1 (PDK1) by modulating the phosphorylation‐dependent conformational transition. The mechanism of action of these compounds was characterized by mutagenesis of PDK1, synthesis of compound analogs, interaction‐displacement studies and isothermal titration calorimetry experiments. Our results raise the possibility of developing drugs that target the AGC kinases via a novel mode of action and may inspire future rational development of compounds with the ability to modulate phosphorylation‐dependent conformational transitions in other proteins.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>France</li></country><region><li>Sarre (Land)</li><li>Île-de-France</li></region><settlement><li>Paris</li><li>Sarrebruck</li></settlement></list><tree><country name="Allemagne"><region name="Sarre (Land)"><name sortKey="Engel, Matthias" sort="Engel, Matthias" uniqKey="Engel M" first="Matthias" last="Engel">Matthias Engel</name></region><name sortKey="Adrian, Iris" sort="Adrian, Iris" uniqKey="Adrian I" first="Iris" last="Adrian">Iris Adrian</name><name sortKey="Biondi, Ricardo M" sort="Biondi, Ricardo M" uniqKey="Biondi R" first="Ricardo M" last="Biondi">Ricardo M. Biondi</name><name sortKey="Biondi, Ricardo M" sort="Biondi, Ricardo M" uniqKey="Biondi R" first="Ricardo M" last="Biondi">Ricardo M. Biondi</name><name sortKey="Hartmann, Rolf W" sort="Hartmann, Rolf W" uniqKey="Hartmann R" first="Rolf W" last="Hartmann">Rolf W. Hartmann</name><name sortKey="Hindie, Valerie" sort="Hindie, Valerie" uniqKey="Hindie V" first="Valerie" last="Hindie">Valerie Hindie</name><name sortKey="Idrissova, Leila" sort="Idrissova, Leila" uniqKey="Idrissova L" first="Leila" last="Idrissova">Leila Idrissova</name><name sortKey="Imig, Jochen" sort="Imig, Jochen" uniqKey="Imig J" first="Jochen" last="Imig">Jochen Imig</name><name sortKey="Lopez Arcia, Laura A" sort="Lopez Arcia, Laura A" uniqKey="Lopez Arcia L" first="Laura A" last="Lopez-Garcia">Laura A. Lopez-Garcia</name><name sortKey="Nastainczyk, Wolfgang" sort="Nastainczyk, Wolfgang" uniqKey="Nastainczyk W" first="Wolfgang" last="Nastainczyk">Wolfgang Nastainczyk</name><name sortKey="Piiper, Albrecht" sort="Piiper, Albrecht" uniqKey="Piiper A" first="Albrecht" last="Piiper">Albrecht Piiper</name><name sortKey="Stroba, Adriana" sort="Stroba, Adriana" uniqKey="Stroba A" first="Adriana" last="Stroba">Adriana Stroba</name><name sortKey="Zeuzem, Stefan" sort="Zeuzem, Stefan" uniqKey="Zeuzem S" first="Stefan" last="Zeuzem">Stefan Zeuzem</name></country><country name="France"><region name="Île-de-France"><name sortKey="Hindie, Valerie" sort="Hindie, Valerie" uniqKey="Hindie V" first="Valerie" last="Hindie">Valerie Hindie</name></region><name sortKey="Alzari, Pedro M" sort="Alzari, Pedro M" uniqKey="Alzari P" first="Pedro M" last="Alzari">Pedro M. Alzari</name><name sortKey="Schaeffer, Francis" sort="Schaeffer, Francis" uniqKey="Schaeffer F" first="Francis" last="Schaeffer">Francis Schaeffer</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonFranceV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002A32 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 002A32 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonFranceV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= ISTEX:8BF57A0158BD8FD4B2E43B4F90225E7A49D8E459
|texte= Allosteric activation of the protein kinase PDK1 with low molecular weight compounds
}}
| This area was generated with Dilib version V0.6.29. |  |