Sandbox Reserved 825: Difference between revisions
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As a member of '''the phosphatidylinositol kinase-related kinases''' ([http://en.wikipedia.org/wiki/Phosphatidylinositol_3-kinase-related_kinase PIKK]) the mammalian targert of rapamycin ([http://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin mTOR]) | As a member of '''the phosphatidylinositol kinase-related kinases''' ([http://en.wikipedia.org/wiki/Phosphatidylinositol_3-kinase-related_kinase PIKK]) the mammalian targert of rapamycin ([http://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin mTOR]) | ||
is a multi domain protein which is involved in the regulation of cell growth and is an important target of survival | 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. | signals in cancer cells. | ||
The sequence of the 2549 residues is '''highly conserved''' across eukaryotes (40-60% precent sequence identity). | The sequence of the 2549 residues is '''highly conserved''' across eukaryotes (40-60% precent sequence identity). | ||
The protein consists of several functional | The protein consists of several functional domains:<br />At the N-terminus there are twelve [http://en.wikipedia.org/wiki/HEAT_repeat_domain HEAT] repeats followed by a | ||
central [http://en.wikipedia.org/wiki/Focal_adhesion_targeting_region FAT] domain (residues 1513-1910), a '''FRB domain''' (residues 2015-2114) a [http://en.wikipedia.org/?title=Serine/threonine-specific_protein_kinase serine-threonine kinase] domain | central [http://en.wikipedia.org/wiki/Focal_adhesion_targeting_region FAT] domain (residues 1513-1910), a '''FRB domain''' (residues 2015-2114) a [http://en.wikipedia.org/?title=Serine/threonine-specific_protein_kinase serine-threonine kinase] domain | ||
(residues 2181-2484) and a C-terminal FATC domain (residues 2515-2549). | (residues 2181-2484) and a C-terminal FATC domain (residues 2515-2549). | ||
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Helix 3 contains a <scene name='56/568023/Helix_3_bend_residues/1'>bend</scene> of approximately 45° and its N-terminal half is largely disordered. | Helix 3 contains a <scene name='56/568023/Helix_3_bend_residues/1'>bend</scene> of approximately 45° and its N-terminal half is largely disordered. | ||
The surface structure reveals two main interaction sites, a shallow <scene name='56/568023/Hydrophobic_pocket/1'>hydrophobic patch</scene> made up | The surface structure reveals two main interaction sites, a shallow <scene name='56/568023/Hydrophobic_pocket/1'>hydrophobic patch</scene> made up of helix 1 and helix 4 | ||
which is responsible for the binding of rapamycin and a <scene name='56/568023/Deep_cleft_helix_2_and_3/1'>deep cleft</scene> between helix 2 and helix 3. This cleft contains | which is responsible for the binding of rapamycin and a <scene name='56/568023/Deep_cleft_helix_2_and_3/1'>deep cleft</scene> between helix 2 and helix 3. This cleft contains | ||
charged and hydrophobic residues and is expected to function as a binding site for small molecules to regulate | charged and hydrophobic residues and is expected to function as a binding site for small molecules to regulate | ||
mTOR activity. | mTOR activity. | ||
The binding sites for '''phosphatidic acid''' and '''rapamycin''' show significant <scene name='56/568023/Overlapping_residues/3'>overlapping</scene> suggesting that rapamycin inhibits kinase activity of mTOR by blocking access of the activator phosphatidic acid.<br /> There are five amino acids whose side chains are exposed to the solvent and who play an active role in phosphatidic acid binding (E2031, F2039, Y2105, H2106, R2109). Those are the residues that also take part in rapamycin binding. Three amino acids at the FRB domain contribute passively to the binding of the activator (L2031, S2035, W2101). The positive charged arginine residue '''R2109''' plays a key role in the binding of phosphatidic acid as it binds to the negetively charged phosphate group. | The binding sites for '''phosphatidic acid''' and '''rapamycin''' show significant <scene name='56/568023/Overlapping_residues/3'>overlapping</scene> (E2031, F2039, Y2105, H2106, R2109) suggesting that rapamycin inhibits kinase activity of mTOR by blocking access of the activator phosphatidic acid.<br /> There are five amino acids whose side chains are exposed to the solvent and who play an active role in phosphatidic acid binding (E2031, F2039, Y2105, H2106, R2109). Those are the residues that also take part in rapamycin binding. Three amino acids at the FRB domain contribute passively to the binding of the activator (L2031, S2035, W2101). The positive charged arginine residue '''R2109''' plays a key role in the binding of phosphatidic acid as it binds to the negetively charged phosphate group. | ||
Other molecules like the novel class inhibitor '''HTS-1''' (4-[6-{[(1S,2R)-2-(benzyloxy)cyclopentyl]acety}-4-(2-thienyl)pyridin-2-yl]-4-oxobutanoic acid) | Other molecules like the novel class inhibitor '''HTS-1''' (4-[6-{[(1S,2R)-2-(benzyloxy)cyclopentyl]acety}-4-(2-thienyl)pyridin-2-yl]-4-oxobutanoic acid) | ||
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MTOR has been found to form two distinct complexes called '''mTOR complex 1''' ([http://en.wikipedia.org/wiki/MTORC1 mTORC1]) and '''mTOR complex 2''' ([http://en.wikipedia.org/wiki/MTORC2 mTORC2]).<br /> | MTOR has been found to form two distinct complexes called '''mTOR complex 1''' ([http://en.wikipedia.org/wiki/MTORC1 mTORC1]) and '''mTOR complex 2''' ([http://en.wikipedia.org/wiki/MTORC2 mTORC2]).<br /> | ||
While mTORC1 is bound and inhibited by rapamycin mTORC2 is not affected by rapamycin presence. <ref> PMID: 20005306 </ref> Depending on the formed complex mTOR activity can provoke different cellular responses | While mTORC1 is bound and inhibited by rapamycin mTORC2 is not affected by rapamycin presence. <ref> PMID: 20005306 </ref> Depending on the formed complex mTOR activity can provoke different cellular responses. MTORC1 for example leads to activation of translation and inhibition of autophagy. <br /> | ||
MTORC2 on the other hand regulates the assembly of cytoskeleton and activates the '''Protein Kinase B''' ([http://en.wikipedia.org/wiki/Protein_Kinase_B Akt]) which plays a central role in the phosphoinositide 3-kinase [http://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway pathway] , which leads to cell survival and [http://en.wikipedia.org/wiki/S_phase S-phase] entry and is revealed to be overactive in many human cancers. <ref> PMID: 12040186 </ref><br /> | MTORC2 on the other hand regulates the assembly of cytoskeleton and activates the '''Protein Kinase B''' ([http://en.wikipedia.org/wiki/Protein_Kinase_B Akt]) which plays a central role in the phosphoinositide 3-kinase [http://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway pathway] , which leads to cell survival and [http://en.wikipedia.org/wiki/S_phase S-phase] entry and is revealed to be overactive in many human cancers. <ref> PMID: 12040186 </ref><br /> | ||
