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Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors.

Ikuta M, Kornienko M, Byrne N, Reid JC, Mizuarai S, Kotani H, Munshi SK
Protein Sci 16 2626-35 (2007)
Related entries: 2z7r, 2z7s

Cited: 34 times
EuropePMC logo PMID: 17965187

Abstract

The p90 ribosomal S6 kinases (RSKs) also known as MAPKAP-Ks are serine/threonine protein kinases that are activated by ERK or PDK1 and act as downstream effectors of mitogen-activated protein kinase (MAPK). RSK1, a member of the RSK family, contains two distinct kinase domains in a single polypeptide chain, the regulatory C-terminal kinase domain (CTKD) and the catalytic N-terminal kinase domain (NTKD). Autophosphorylation of the CTKD leads to activation of the NTKD that subsequently phosphorylates downstream substrates. Here we report the crystal structures of the unactivated RSK1 NTKD bound to different ligands at 2.0 A resolution. The activation loop and helix alphaC, key regulatory elements of kinase function, are disordered. The DFG motif of the inactive RSK1 adopts an "active-like" conformation. The beta-PO(4) group in the AMP-PCP complex adopts a unique conformation that may contribute to inactivity of the enzyme. Structures of RSK1 ligand complexes offer insights into the design of novel anticancer agents and into the regulation of the catalytic activity of RSKs.

Articles - 2z7q mentioned but not cited (7)

  1. Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y-box binding protein-1 (YB-1). Reipas KM, Law JH, Couto N, Islam S, Li Y, Li H, Cherkasov A, Jung K, Cheema AS, Jones SJ, Hassell JA, Dunn SE. Oncotarget 4 329-345 (2013)
  2. Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors. Ikuta M, Kornienko M, Byrne N, Reid JC, Mizuarai S, Kotani H, Munshi SK. Protein Sci 16 2626-2635 (2007)
  3. Proteome-wide discovery and characterizations of nucleotide-binding proteins with affinity-labeled chemical probes. Xiao Y, Guo L, Jiang X, Wang Y. Anal Chem 85 3198-3206 (2013)
  4. Structural diversity of the active N-terminal kinase domain of p90 ribosomal S6 kinase 2. Malakhova M, Kurinov I, Liu K, Zheng D, D'Angelo I, Shim JH, Steinman V, Bode AM, Dong Z. PLoS One 4 e8044 (2009)
  5. Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment. Xiong S, Lorenzen K, Couzens AL, Templeton CM, Rajendran D, Mao DYL, Juang YC, Chiovitti D, Kurinov I, Guettler S, Gingras AC, Sicheri F. Structure 26 1101-1115.e6 (2018)
  6. RSK1 vs. RSK2 Inhibitory Activity of the Marine β-Carboline Alkaloid Manzamine A: A Biochemical, Cervical Cancer Protein Expression, and Computational Study. Mayer AMS, Hall ML, Lach J, Clifford J, Chandrasena K, Canton C, Kontoyianni M, Choo YM, Karan D, Hamann MT. Mar Drugs 19 506 (2021)
  7. Marine-Based Candidates as Potential RSK1 Inhibitors: A Computational Study. AlTarabeen M, Al-Balas Q, Albohy A, Müller WEG, Proksch P. Molecules 28 202 (2022)


Reviews citing this publication (4)

  1. AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases. Arencibia JM, Pastor-Flores D, Bauer AF, Schulze JO, Biondi RM. Biochim Biophys Acta 1834 1302-1321 (2013)
  2. Molecular basis for small molecule inhibition of G protein-coupled receptor kinases. Homan KT, Tesmer JJ. ACS Chem Biol 10 246-256 (2015)
  3. RSK3: A regulator of pathological cardiac remodeling. Martinez EC, Passariello CL, Li J, Matheson CJ, Dodge-Kafka K, Reigan P, Kapiloff MS. IUBMB Life 67 331-337 (2015)
  4. The unusual mechanism of inhibition of the p90 ribosomal S6 kinase (RSK) by flavonol rhamnosides. Utepbergenov D, Derewenda ZS. Biochim Biophys Acta 1834 1285-1291 (2013)

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  2. A regulatory mechanism for RSK2 NH(2)-terminal kinase activity. Cho YY, Yao K, Pugliese A, Malakhova ML, Bode AM, Dong Z. Cancer Res 69 4398-4406 (2009)
  3. Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation. Sunami T, Byrne N, Diehl RE, Funabashi K, Hall DL, Ikuta M, Patel SB, Shipman JM, Smith RF, Takahashi I, Zugay-Murphy J, Iwasawa Y, Lumb KJ, Munshi SK, Sharma S. J Biol Chem 285 4587-4594 (2010)
  4. The crystal structures of substrate and nucleotide complexes of Enterococcus faecium aminoglycoside-2''-phosphotransferase-IIa [APH(2'')-IIa] provide insights into substrate selectivity in the APH(2'') subfamily. Young PG, Walanj R, Lakshmi V, Byrnes LJ, Metcalf P, Baker EN, Vakulenko SB, Smith CA. J Bacteriol 191 4133-4143 (2009)
  5. Structural Basis of Ribosomal S6 Kinase 1 (RSK1) Inhibition by S100B Protein: MODULATION OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) SIGNALING CASCADE IN A CALCIUM-DEPENDENT WAY. Gógl G, Alexa A, Kiss B, Katona G, Kovács M, Bodor A, Reményi A, Nyitray L. J Biol Chem 291 11-27 (2016)
  6. Identification of domains responsible for ubiquitin-dependent degradation of dMyc by glycogen synthase kinase 3beta and casein kinase 1 kinases. Galletti M, Riccardo S, Parisi F, Lora C, Saqcena MK, Rivas L, Wong B, Serra A, Serras F, Grifoni D, Pelicci P, Jiang J, Bellosta P. Mol Cell Biol 29 3424-3434 (2009)
  7. Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer. Milosevic N, Kühnemuth B, Mühlberg L, Ripka S, Griesmann H, Lölkes C, Buchholz M, Aust D, Pilarsky C, Krug S, Gress T, Michl P. Neoplasia 15 1354-1362 (2013)
  8. Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 Å crystal structure of the N-terminal domain of RSK2 with bound inhibitor. Utepbergenov D, Derewenda U, Olekhnovich N, Szukalska G, Banerjee B, Hilinski MK, Lannigan DA, Stukenberg PT, Derewenda ZS. Biochemistry 51 6499-6510 (2012)
  9. A Rising Cancer Prevention Target of RSK2 in Human Skin Cancer. Arul N, Cho YY. Front Oncol 3 201 (2013)
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  11. Localization and retention of p90 ribosomal S6 kinase 1 in the nucleus: implications for its function. Gao X, Chaturvedi D, Patel TB. Mol Biol Cell 23 503-515 (2012)
  12. A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells. Gasparini VR, Binatti A, Coppe A, Teramo A, Vicenzetto C, Calabretto G, Barilà G, Barizza A, Giussani E, Facco M, Mustjoki S, Semenzato G, Zambello R, Bortoluzzi S. Blood Cancer J 10 42 (2020)
  13. Allosteric regulation of PKCθ: understanding multistep phosphorylation and priming by ligands in AGC kinases. Seco J, Ferrer-Costa C, Campanera JM, Soliva R, Barril X. Proteins 80 269-280 (2012)
  14. Structural basis for the autoinhibition of the C-terminal kinase domain of human RSK1. Li D, Fu TM, Nan J, Liu C, Li LF, Su XD. Acta Crystallogr D Biol Crystallogr 68 680-685 (2012)
  15. TAK1 inhibition in the DFG-out conformation. Kilty I, Green MP, Bell AS, Brown DG, Dodd PG, Hewson C, Hughes SJ, Phillips C, Ryckmans T, Smith RT, van Hoorn WP, Cohen P, Jones LH. Chem Biol Drug Des 82 500-505 (2013)
  16. Indole RSK inhibitors. Part 1: discovery and initial SAR. Boyer SJ, Burke J, Guo X, Kirrane TM, Snow RJ, Zhang Y, Sarko C, Soleymanzadeh L, Swinamer A, Westbrook J, Dicapua F, Padyana A, Cogan D, Gao A, Xiong Z, Madwed JB, Kashem M, Kugler S, O'Neill MM. Bioorg Med Chem Lett 22 733-737 (2012)
  17. p90 ribosomal S6 kinase 1 (RSK1) and the catalytic subunit of protein kinase A (PKA) compete for binding the pseudosubstrate region of PKAR1alpha: role in the regulation of PKA and RSK1 activities. Gao X, Chaturvedi D, Patel TB. J Biol Chem 285 6970-6979 (2010)
  18. Inhibition of p90RSK activation sensitizes triple-negative breast cancer cells to cisplatin by inhibiting proliferation, migration and EMT. Jin Y, Huynh DTN, Kang KW, Myung CS, Heo KS. BMB Rep 52 706-711 (2019)
  19. Functional Basis and Biophysical Approaches to Characterize the C-Terminal Domain of Human-Ribosomal S6 Kinases-3. Jagilinki BP, Choudhary RK, Thapa PS, Gadewal N, Hosur MV, Kumar S, Varma AK. Cell Biochem Biophys 74 317-325 (2016)
  20. RSK2 Binding Models Delineate Key Features for Activity. Gussio R, Currens MJ, Scudiero DA, Smith JA, Lannigan DA, Shoemaker RH, Zaharevitz DW, Nguyen TL. J Chem Pharm Res 2 587-598 (2010)
  21. Identification of a New Mutation in RSK2, the Gene for Coffin-Lowry Syndrome (CLS), in Two Related Patients with Mild and Atypical Phenotypes. Di Stazio M, Bigoni S, Iuso N, Vuch J, Selvatici R, Ulivi S, d'Adamo PA. Brain Sci 11 1105 (2021)
  22. Evaluation of Pathogenicity and Structural Alterations for the Mutations Identified in the Conserved Region of the C-Terminal Kinase Domain of Human-Ribosomal S6 Kinase 1. Chikhale V, Goswami N, Khan MA, Borah P, Varma AK. ACS Omega 8 16273-16283 (2023)
  23. Experimental and theoretical spectroscopic (FT-IR, FT-Raman, UV-VIS) analysis, natural bonding orbitals and molecular docking studies on 2-bromo-6-methoxynaphthalene: A potential anti-cancer drug. Saji RS, Prasana JC, Muthu S, George J. Heliyon 7 e07213 (2021)


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