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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 mTOR’s 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 mTOR’s 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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