| Structural highlights
4rlo is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.527Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
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[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 2001 Aug 15;20(16):4370-9. PMID:11500364 doi:http://dx.doi.org/10.1093/emboj/20.16.4370
- ↑ Fleckenstein DS, Dirks WG, Drexler HG, Quentmeier H. Tumor necrosis factor receptor-associated factor (TRAF) 4 is a new binding partner for the p70S6 serine/threonine kinase. Leuk Res. 2003 Aug;27(8):687-94. PMID:12801526
- ↑ Richardson CJ, Broenstrup M, Fingar DC, Julich K, Ballif BA, Gygi S, Blenis J. SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol. 2004 Sep 7;14(17):1540-9. PMID:15341740 doi:http://dx.doi.org/10.1016/j.cub.2004.08.061
- ↑ Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 2004 Apr 21;23(8):1761-9. Epub 2004 Apr 8. PMID:15071500 doi:http://dx.doi.org/10.1038/sj.emboj.7600193
- ↑ Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2004 Jan;24(1):200-16. PMID:14673156
- ↑ Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005 Nov 18;123(4):569-80. PMID:16286006 doi:http://dx.doi.org/S0092-8674(05)01157-8
- ↑ Zhang HH, Lipovsky AI, Dibble CC, Sahin M, Manning BD. S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Mol Cell. 2006 Oct 20;24(2):185-97. PMID:17052453 doi:http://dx.doi.org/10.1016/j.molcel.2006.09.019
- ↑ Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006 Oct 20;314(5798):467-71. PMID:17053147 doi:10.1126/science.1130276
- ↑ Djouder N, Metzler SC, Schmidt A, Wirbelauer C, Gstaiger M, Aebersold R, Hess D, Krek W. S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates a negative feedback program that counters S6K1 survival signaling. Mol Cell. 2007 Oct 12;28(1):28-40. PMID:17936702 doi:http://dx.doi.org/10.1016/j.molcel.2007.08.010
- ↑ Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem. 2008 Dec 19;283(51):35375-82. doi: 10.1074/jbc.M806480200. Epub 2008, Oct 24. PMID:18952604 doi:http://dx.doi.org/10.1074/jbc.M806480200
- ↑ Kim D, Akcakanat A, Singh G, Sharma C, Meric-Bernstam F. Regulation and localization of ribosomal protein S6 kinase 1 isoforms. Growth Factors. 2009 Feb;27(1):12-21. doi: 10.1080/08977190802556986. PMID:19085255 doi:http://dx.doi.org/10.1080/08977190802556986
- ↑ Dibble CC, Asara JM, Manning BD. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol. 2009 Nov;29(21):5657-70. Epub 2009 Aug 31. PMID:19720745 doi:http://dx.doi.org/MCB.00735-09
- ↑ Julien LA, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol. 2010 Feb;30(4):908-21. doi: 10.1128/MCB.00601-09. Epub 2009 Dec 7. PMID:19995915 doi:http://dx.doi.org/10.1128/MCB.00601-09
- ↑ Treins C, Warne PH, Magnuson MA, Pende M, Downward J. Rictor is a novel target of p70 S6 kinase-1. Oncogene. 2010 Feb 18;29(7):1003-16. doi: 10.1038/onc.2009.401. Epub 2009 Nov 23. PMID:19935711 doi:http://dx.doi.org/10.1038/onc.2009.401
- ↑ 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. Development of Organometallic S6K1 Inhibitors. J Med Chem. 2015 Jan 8;58(1):305-14. doi: 10.1021/jm5011868. Epub 2014 Nov 13. PMID:25356520 doi:http://dx.doi.org/10.1021/jm5011868
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