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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,
Online J Bioinformatics 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