Activating mutations in TOR are in similar structures as oncogenic mutations in PI3KCalpha.
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.
Sturgill
Thomas W
TW
Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA. tws7w@virginia.edu
Hall
Michael N
MN
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000201:enzymology; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D058570:TOR Serine-Threonine Kinases
D000255:Adenosine Triphosphate; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C513100:tor2 protein, S pombe; C500749:target of rapamycin protein, S cerevisiae