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Activating mutations in TOR are in similar structures as oncogenic mutations in PI3KCalpha.

Identifieur interne : 001548 ( Main/Exploration ); précédent : 001547; suivant : 001549

Activating mutations in TOR are in similar structures as oncogenic mutations in PI3KCalpha.

Auteurs : Thomas W. Sturgill [États-Unis] ; Michael N. Hall

Source :

RBID : pubmed:19902965

Descripteurs français

English descriptors

Abstract

TOR (Target of Rapamycin) is a highly conserved Ser/Thr kinase and a central controller of cell growth. Using the crystal structure of the related lipid kinase PI3KCgamma, we built a model of the catalytic region of TOR, from the FAT domain to near the end of the FATC domain. The model reveals that activating mutations in TOR, identified in yeast in a genetic selection for Rheb-independence, correspond to hotspots for oncogenic mutations in PI3KCalpha. The activating mutations are in the catalytic domain (helices kalpha3, kalpha9, kalpha11) and the helical domain of TOR. Docking studies with small molecule inhibitors (PP242, NVP-BEZ235, and Ku-0063794) show that drugs currently in development utilize a novel pharmacophore space to achieve specificity. Thus, our model provides insight on the regulation of TOR and may be useful in the design of new anticancer drugs.

DOI: 10.1021/cb900193e
PubMed: 19902965
PubMed Central: PMC2796128


Affiliations:


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Le document en format XML

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<term>Crystallography, X-Ray (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Intracellular Signaling Peptides and Proteins (chemistry)</term>
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<term>Intracellular Signaling Peptides and Proteins (metabolism)</term>
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<term>Phosphatidylinositol 3-Kinases (genetics)</term>
<term>Phosphatidylinositol 3-Kinases (metabolism)</term>
<term>Protein Binding (MeSH)</term>
<term>Protein Conformation (MeSH)</term>
<term>Protein Kinase Inhibitors (chemistry)</term>
<term>Protein Kinase Inhibitors (metabolism)</term>
<term>Protein-Serine-Threonine Kinases (chemistry)</term>
<term>Protein-Serine-Threonine Kinases (genetics)</term>
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<term>Schizosaccharomyces pombe Proteins (genetics)</term>
<term>Schizosaccharomyces pombe Proteins (metabolism)</term>
<term>Sequence Alignment (MeSH)</term>
<term>TOR Serine-Threonine Kinases (MeSH)</term>
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<term>Adénosine triphosphate (métabolisme)</term>
<term>Alignement de séquences (MeSH)</term>
<term>Animaux (MeSH)</term>
<term>Conformation des protéines (MeSH)</term>
<term>Cristallographie aux rayons X (MeSH)</term>
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<term>Données de séquences moléculaires (MeSH)</term>
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<term>Inhibiteurs de protéines kinases (métabolisme)</term>
<term>Liaison aux protéines (MeSH)</term>
<term>Modèles moléculaires (MeSH)</term>
<term>Mutation (MeSH)</term>
<term>Phosphatidylinositol 3-kinases (composition chimique)</term>
<term>Phosphatidylinositol 3-kinases (génétique)</term>
<term>Phosphatidylinositol 3-kinases (métabolisme)</term>
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<term>Protein-Serine-Threonine Kinases (génétique)</term>
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<term>Protéines de Schizosaccharomyces pombe (génétique)</term>
<term>Protéines de Schizosaccharomyces pombe (métabolisme)</term>
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<term>Protéines et peptides de signalisation intracellulaire (métabolisme)</term>
<term>Saccharomyces cerevisiae (enzymologie)</term>
<term>Schizosaccharomyces (enzymologie)</term>
<term>Séquence d'acides aminés (MeSH)</term>
<term>Sérine-thréonine kinases TOR (MeSH)</term>
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<term>Protein-Serine-Threonine Kinases</term>
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<term>Phosphatidylinositol 3-kinases</term>
<term>Protein-Serine-Threonine Kinases</term>
<term>Protéines de Saccharomyces cerevisiae</term>
<term>Protéines de Schizosaccharomyces pombe</term>
<term>Protéines et peptides de signalisation intracellulaire</term>
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<term>Protein-Serine-Threonine Kinases</term>
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<term>Protéines de Schizosaccharomyces pombe</term>
<term>Protéines et peptides de signalisation intracellulaire</term>
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<term>Adénosine triphosphate</term>
<term>Inhibiteurs de protéines kinases</term>
<term>Phosphatidylinositol 3-kinases</term>
<term>Protein-Serine-Threonine Kinases</term>
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<term>Animals</term>
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<term>Crystallography, X-Ray</term>
<term>Humans</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
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<term>Cristallographie aux rayons X</term>
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<term>Données de séquences moléculaires</term>
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<term>Modèles moléculaires</term>
<term>Mutation</term>
<term>Séquence d'acides aminés</term>
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<div type="abstract" xml:lang="en">TOR (Target of Rapamycin) is a highly conserved Ser/Thr kinase and a central controller of cell growth. Using the crystal structure of the related lipid kinase PI3KCgamma, we built a model of the catalytic region of TOR, from the FAT domain to near the end of the FATC domain. The model reveals that activating mutations in TOR, identified in yeast in a genetic selection for Rheb-independence, correspond to hotspots for oncogenic mutations in PI3KCalpha. The activating mutations are in the catalytic domain (helices kalpha3, kalpha9, kalpha11) and the helical domain of TOR. Docking studies with small molecule inhibitors (PP242, NVP-BEZ235, and Ku-0063794) show that drugs currently in development utilize a novel pharmacophore space to achieve specificity. Thus, our model provides insight on the regulation of TOR and may be useful in the design of new anticancer drugs.</div>
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