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This Sandbox is Reserved from 06/12/2018, through 30/06/2019 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1480 through Sandbox Reserved 1543.

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FKBP12-rapamycin binding domain of mTOR

FRB domain of mTOR (or 2NPU) is responsible for the binding of the inhibitory cyclic macrolide Rapamycin

Introduction

spinqualitylabelsall models Cartoon model of the FRB domain of mTOR Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

As a member of the phosphatidylinositol kinase-related kinases (PIKK)* the mammalian targert of rapamycin (mTOR)* is a multi domain protein which is involved in the regulation of cell growth and is an important target of survival signals in cancer cells. The sequence of the 2549 residues is highly conserved across eukaryotes (40-60% precent sequence identity). The protein consists of several functional domains: At the N-terminus there are 12 HEAT* repeats followed by a central FAT* domain (residues 1513-1910), a FRB domain (residues 2015-2114) a serine-threonine kinase domain (residues 2181-2484) and a C-terminal FATC* domain (residues 2515-2549). The FKBP12-rapamycin binding (FRB) domain mediates ligand-dependent regulation of the kinase domain by binding different molecules. FRB binds the inhibitory cyclic macroloide* rapamycin in complex with the small peptidyl-prolyl cis-trans isomerase FKBP12* leading to a decreased activity of the kinase domain. Due to its inhibitory effect rapamycin has been a widely used tool for studying mTOR. FRB is also capable of binding the activator phosphatidic acid* and small molecules, for example amino acids like leucine.

Structure of FRB

spinqualitylabelsall models Insert caption here Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

The FRB domain is made up of an disordered domain (greenlink) and a four α-helices bundle joined by short loops (, α2, α3, α4) (Leone et al., 2006). Recent examinations show that the N-terminal half of helix 3 is largely disordered (Veverka et al., 2008).

And now let us try to implement a scence that highlights the of the alpha 1 and alpha 4 helices of the FRB domain