Sandbox Reserved 825: Difference between revisions
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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 />The positive charged arginine residue '''R2109''' plays a key role in the binding of phosphatidic acid as it binds to the negetively charged phosphate | 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 of phosphatidic acid. | ||
group of phosphatidic acid. | |||
[[Image:FRB Phosphatidic Acid.png|upright=1.25|center|thumb| Fig.2 A representative view of phosphatidic acid docked into its binding site on the FRB domain.]] | [[Image:FRB Phosphatidic Acid.png|upright=1.25|center|thumb| Fig.2 A representative view of phosphatidic acid docked into its binding site on the FRB domain.]] | ||
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Other molecules like the novel class inhibitor '''HTS-1''' (4-[6-{[(1S,2R)-2-(benzyloxy)cyclopentyl]acety}-4-(2-thienyl)pyridin-2-yl]-4-xobutanoic 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-xobutanoic acid) | ||
are also capable of inhibiting the kinase activity of mTOR by partially occupying the binding site for phosphatidic acid. | are also capable of inhibiting the kinase activity of mTOR by partially occupying the binding site for phosphatidic acid. | ||
There are <scene name='56/568023/Hts-1_binding_residues/1'>ten</scene> residues at the FRB domain that are predominantly involved in HTS-1 binding. At least <scene name='56/568023/Ovelap_pa_and_hts-1/1'>six</scene> of those residues also take part in phosphatidic acid | There are <scene name='56/568023/Hts-1_binding_residues/1'>ten</scene> residues at the FRB domain that are predominantly involved in HTS-1 binding (actively: E2032, S2035, Y2038, F2039, T2098, W2101, Y2105, F2108, passively: H2028, L2031). At least <scene name='56/568023/Ovelap_pa_and_hts-1/1'>six</scene> of those residues also take part in phosphatidic acid | ||
binding. <ref> DOI: 10.1007/s12154-008-0003-5 | binding (L2031, W2101, E2032, F2039, Y2105, S2035). <ref> DOI: 10.1007/s12154-008-0003-5 | ||
</ref> | </ref> | ||
[[Image:FRB HTS-1 Rapamycin.png|center|upright=2| thumb| Fig.3 A representative view of the mTOR inhibitor HTS-1 docked into its binding site on the FRB domain on the left. On the right, the location and conformation of rapamycin bound to the FRB domain in the ternary complex formed with FKBP12 is illustrated, with the domain shown in the same orientation as on the left.]] | [[Image:FRB HTS-1 Rapamycin.png|center|upright=2| thumb| Fig.3 A representative view of the mTOR inhibitor HTS-1 docked into its binding site on the FRB domain on the left. On the right, the location and conformation of rapamycin bound to the FRB domain in the ternary complex formed with FKBP12 is illustrated, with the domain shown in the same orientation as on the left.]] | ||
