4drh | pdb_00004drh

Co-crystal structure of the PPIase domain of FKBP51, Rapamycin and the FRB fragment of mTOR at low pH

spinqualitylabelsall models 4drh, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4drh is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: RAP, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [FKBP5_HUMAN] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. Publication Abstract from PubMed The immunosuppressant and anti-cancer drug rapamycin works by inducing inhibitory protein complexes with the kinase mTOR, an important regulator of growth and proliferation. The obligatory accessory partner of rapamycin is believed to be FKBP12. Here we show that rapamycin complexes of larger FKBP protein family members can tightly bind to mTOR and potently inhibit its kinase activity. Co-crystal structures with FKBP51 and FKBP52 reveal the modified molecular binding mode of these alternative ternary complexes in detail. In cellular model systems, FKBP12 can be functionally replaced by larger FKBPs. When rapamycin dosage is limiting, mTOR inhibition of S6K phosphorylation can be enhanced by FKBP51 overexpression in mammalian cells, whereas FKBP12 is dispensable. FKBP51 could also enable the rapamycin-induced hyperphosphorylation of Akt, which depended on higher FKBP levels compared to rapamycin-induced inhibition of S6K phosphorylation. These insights provide a mechanistic rationale for a preferential mTOR inhibition in specific cells or tissues types by engaging specific FKBP homologs. Large FK506-binding Proteins Shape the Pharmacology of Rapamycin.,Marz AM, Fabian AK, Kozany C, Bracher A, Hausch F Mol Cell Biol. 2013 Jan 28. PMID:23358420 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also FKBP 3D structures Serine/threonine protein kinase 3D structures

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