4rlo
From Proteopedia
(Difference between revisions)
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| - | ''' | + | ==Human p70s6k1 with ruthenium-based inhibitor EM5== |
| + | <StructureSection load='4rlo' size='340' side='right' caption='[[4rlo]], [[Resolution|resolution]] 2.53Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4rlo]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RLO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RLO FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3T3:[(AMINO-KAPPAN)METHANETHIOLATO](3-FLUORO-9-HYDROXYPYRIDO[2,3-A]PYRROLO[3,4-C]CARBAZOLE-5,7(6H,12H)-DIONATO-KAPPA~2~N,N)(1,4,7-TRITHIONANE-KAPPA~3~S~1~,S~4~,S~7~)RUTHENIUM'>3T3</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=STU:STAUROSPORINE'>STU</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rlp|4rlp]]</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=4rlo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rlo OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rlo RCSB], [http://www.ebi.ac.uk/pdbsum/4rlo PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/KS6B1_HUMAN KS6B1_HUMAN]] Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the preinitiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at 'Thr-412', which is proposed to be a negative feedback mechanism for the RPS6KB1 anti-apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1-2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin.<ref>PMID:11500364</ref> <ref>PMID:12801526</ref> <ref>PMID:15341740</ref> <ref>PMID:15071500</ref> <ref>PMID:14673156</ref> <ref>PMID:16286006</ref> <ref>PMID:17052453</ref> <ref>PMID:17053147</ref> <ref>PMID:17936702</ref> <ref>PMID:18952604</ref> <ref>PMID:19085255</ref> <ref>PMID:19720745</ref> <ref>PMID:19995915</ref> <ref>PMID:19935711</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previously used to target other kinases. Biochemical data demonstrate that EM5 and FL772 inhibit the kinase with IC50 value in the low nanomolar range at 100 muM ATP and that the more potent FL772 compound has a greater than 100-fold specificity over S6K2. The crystal structures of S6K1 bound to staurosporine, EM5, and FL772 reveal that the EM5 and FL772 inhibitors bind in the ATP binding pocket and make S6K1-specific contacts, resulting in changes to the p-loop, alphaC helix, and alphaD helix when compared to the staurosporine-bound structure. Cellular data reveal that FL772 is able to inhibit S6K phosphorylation in yeast cells. Together, these studies demonstrate that potent, selective, and cell permeable S6K1 inhibitors can be prepared and provide a scaffold for future development of S6K inhibitors with possible therapeutic applications. | ||
| - | + | Development of Organometallic S6K1 Inhibitors.,Qin J, Rajaratnam R, Feng L, Salami J, Barber-Rotenberg JS, Domsic J, Reyes-Uribe P, Liu H, Dang W, Berger SL, Villanueva J, Meggers E, Marmorstein R J Med Chem. 2015 Jan 8;58(1):305-14. doi: 10.1021/jm5011868. Epub 2014 Nov 13. PMID:25356520<ref>PMID:25356520</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | + | <references/> | |
| - | + | __TOC__ | |
| - | [[Category: | + | </StructureSection> |
| + | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Barber-Rotenberg, J]] | [[Category: Barber-Rotenberg, J]] | ||
| + | [[Category: Domsic, J F]] | ||
[[Category: Marmorstein, R]] | [[Category: Marmorstein, R]] | ||
[[Category: Qin, J]] | [[Category: Qin, J]] | ||
| + | [[Category: Salami, J]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 16:48, 21 January 2015
Human p70s6k1 with ruthenium-based inhibitor EM5
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