5gpg
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Co-crystal structure of the FK506 binding domain of human FKBP25, Rapamycin and the FRB domain of human mTOR== | |
| + | <StructureSection load='5gpg' size='340' side='right' caption='[[5gpg]], [[Resolution|resolution]] 1.67Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5gpg]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5GPG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5GPG FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RAP:RAPAMYCIN+IMMUNOSUPPRESSANT+DRUG'>RAP</scene></td></tr> | ||
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAS:S-(DIMETHYLARSENIC)CYSTEINE'>CAS</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5gpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gpg OCA], [http://pdbe.org/5gpg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5gpg RCSB], [http://www.ebi.ac.uk/pdbsum/5gpg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5gpg ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/FKBP3_HUMAN FKBP3_HUMAN]] FK506- and rapamycin-binding proteins (FKBPs) constitute a family of receptors for the two immunosuppressants which inhibit T-cell proliferation by arresting two distinct cytoplasmic signal transmission pathways. PPIases accelerate the folding of proteins. [[http://www.uniprot.org/uniprot/MTOR_HUMAN 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'.<ref>PMID:12150925</ref> <ref>PMID:12150926</ref> <ref>PMID:12231510</ref> <ref>PMID:12087098</ref> <ref>PMID:14651849</ref> <ref>PMID:12718876</ref> <ref>PMID:15268862</ref> <ref>PMID:15545625</ref> <ref>PMID:15467718</ref> <ref>PMID:15718470</ref> <ref>PMID:18925875</ref> <ref>PMID:18762023</ref> <ref>PMID:18497260</ref> <ref>PMID:20537536</ref> <ref>PMID:20516213</ref> <ref>PMID:21659604</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Mammalian target of rapamycin (mTOR) signaling is a core pathway in cellular metabolism, and control of the mTOR pathway by rapamycin shows potential for the treatment of metabolic diseases. In this study, we employed a new proximity biotin-labeling method using promiscuous biotin ligase (pBirA) to identify unknown elements in the rapamycin-induced interactome on the FK506-rapamycin binding (FRB) domain in living cells. FKBP25 showed the strongest biotin labeling by FRB-pBirA in the presence of rapamycin. Immunoprecipitation and immunofluorescence experiments confirmed that endogenous FKBP25 has a rapamycin-induced physical interaction with the FRB domain. Furthermore, the crystal structure of the ternary complex of FRB-rapamycin-FKBP25 was determined at 1.67-A resolution. In this crystal structure we found that the conformational changes of FRB generate a hole where there is a methionine-rich space, and covalent metalloid coordination was observed at C2085 of FRB located at the bottom of the hole. Our results imply that FKBP25 might have a unique physiological role related to metallomics in mTOR signaling. | ||
| - | + | Proximity-Directed Labeling Reveals a New Rapamycin-Induced Heterodimer of FKBP25 and FRB in Live Cells.,Lee SY, Lee H, Lee HK, Lee SW, Ha SC, Kwon T, Seo JK, Lee C, Rhee HW ACS Cent Sci. 2016 Aug 24;2(8):506-16. doi: 10.1021/acscentsci.6b00137. Epub 2016, Aug 12. PMID:27610411<ref>PMID:27610411</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5gpg" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Peptidylprolyl isomerase]] | ||
| + | [[Category: Lee, C W]] | ||
| + | [[Category: Lee, H B]] | ||
| + | [[Category: Lee, S Y]] | ||
| + | [[Category: Rhee, H W]] | ||
| + | [[Category: Complex]] | ||
| + | [[Category: Isomerase-transferase complex]] | ||
| + | [[Category: Kinase]] | ||
Revision as of 17:38, 19 October 2016
Co-crystal structure of the FK506 binding domain of human FKBP25, Rapamycin and the FRB domain of human mTOR
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