4dri

Co-crystal structure of the PPIase domain of FKBP51, Rapamycin and the FRB fragment of mTORCo-crystal structure of the PPIase domain of FKBP51, Rapamycin and the FRB fragment of mTOR

Structural highlights 4dri is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: Related: 4drh, 4drj Gene: AIG6, FKBP5, FKBP51 (HUMAN), FRAP, FRAP1, FRAP2, MTOR, RAFT1, RAPT1 (HUMAN) Activity: Peptidylprolyl isomerase, with EC number 5.2.1.8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [FKBP5_HUMAN] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. [MTOR_HUMAN] Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B and the inhibitor of translation initiation PDCD4. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 a RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'. 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 FK506 binding protein Serine/threonine protein kinase

spinqualitylabelsall models 4dri, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image