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OJBTM

 Online Journal of Bioinformatics © 

Volume 11 (1): 128-144, 2010


Structural model of the mammalian target of rapamycin (mTOR) kinase domain

 

Anne Tobak1, Sonia Arora2, and William J. Welsh1*

 

1 Department of Pharmacology, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School (UMDNJ-WJMS) & Informatics Institute of UMDNJ, 675 Hoes Lane, Piscataway, NJ 08854, USA, 2 NJ Center for Science, Technology and Mathematics, Kean University, 1000 Morris Avenue, Union, NJ 07083, USA

 

ABstract

 

Tobak A, Arora S, Welsh WJ., Structural model of the mammalian target of rapamycin (mTOR) kinase domain, Onl J Bioinform., 11 (1):128-144, 2010. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in the regulation of protein translation and cell proliferation.  Based on signals received from nutrition, growth factors and insulin, mTOR controls cell growth accordingly and is therefore a key target for anticancer therapeutics and numerous other clinically relevant applications.  Two regions of interest are the FRB domain, where mTORís natural ligand rapamycin binds when in complex with FKBP12, and the ATP-binding site located within the kinase domain. Some cancer cells have shown resistance to the inhibitory effects of rapamycin and its analogues, while other known kinase domain inhibitors generally lack stability and specificity. Clearly, there is a need for kinase domain-targeted mTOR inhibitors as potential therapeutics. Efforts to discover mTOR kinase-targeted inhibitors using structure-based design approaches have been impeded by the absence of a high-resolution x-ray crystal structure of the mTOR kinase domain. Here we describe the construction of a computational structural model of the mTOR kinase domain. Computational docking of ATP as well as known mTOR kinase inhibitors wortmannin and LY294002 into mTORís putative ligand binding pocket reveals several residues that might be critical for tight binding and inhibitory activity.

 

Keywords: mTOR, homology modeling, docking, wortmannin, LY294002, PI3K, kinase domain


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