3g51 › Citations

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)
Cited: 26 times
EuropePMC logo PMID: 19956600

Abstract

The p90 ribosomal protein kinase 2 (RSK2) is a highly expressed Ser/Thr kinase activated by growth factors and is involved in cancer cell proliferation and tumor promoter-induced cell transformation. RSK2 possesses two non-identical kinase domains, and the structure of its N-terminal domain (NTD), which is responsible for phosphorylation of a variety of substrates, is unknown. The crystal structure of the NTD RSK2 was determined at 1.8 A resolution in complex with AMP-PNP. The N-terminal kinase domain adopted a unique active conformation showing a significant structural diversity of the kinase domain compared to other kinases. The NTD RSK2 possesses a three-stranded betaB-sheet inserted in the N-terminal lobe, resulting in displacement of the alphaC-helix and disruption of the Lys-Glu interaction, classifying the kinase conformation as inactive. The purified protein was phosphorylated at Ser227 in the T-activation loop and exhibited in vitro kinase activity. A key characteristic is the appearance of a new contact between Lys216 (betaB-sheet) and the beta-phosphate of AMP-PNP. Mutation of this lysine to alanine impaired both NTDs in vitro and full length RSK2 ex vivo activity, emphasizing the importance of this interaction. Even though the N-terminal lobe undergoes structural re-arrangement, it possesses an intact hydrophobic groove formed between the alphaC-helix, the beta4-strand, and the betaB-sheet junction, which is occupied by the N-terminal tail. The presence of a unique betaB-sheet insert in the N-lobe suggests a different type of activation mechanism for RSK2.

Reviews - 3g51 mentioned but not cited (2)

  1. 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)
  2. Therapeutic targeting of p90 ribosomal S6 kinase. Wright EB, Lannigan DA. Front Cell Dev Biol 11 1297292 (2023)

Articles - 3g51 mentioned but not cited (11)

  1. 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)
  2. Prediction of molecular targets of cancer preventing flavonoid compounds using computational methods. Chen H, Yao K, Nadas J, Bode AM, Malakhova M, Oi N, Li H, Lubet RA, Dong Z. PLoS One 7 e38261 (2012)
  3. Identification of quercitrin as an inhibitor of the p90 S6 ribosomal kinase (RSK): structure of its complex with the N-terminal domain of RSK2 at 1.8 Å resolution. Derewenda U, Artamonov M, Szukalska G, Utepbergenov D, Olekhnovich N, Parikh HI, Kellogg GE, Somlyo AV, Derewenda ZS. Acta Crystallogr D Biol Crystallogr 69 266-275 (2013)
  4. A case of convergent evolution: Several viral and bacterial pathogens hijack RSK kinases through a common linear motif. Sorgeloos F, Peeters M, Hayashi Y, Borghese F, Capelli N, Drappier M, Cesaro T, Colau D, Stroobant V, Vertommen D, de Bodt G, Messe S, Forné I, Mueller-Planitz F, Collet JF, Michiels T. Proc Natl Acad Sci U S A 119 e2114647119 (2022)
  5. Carnosol suppresses patient-derived gastric tumor growth by targeting RSK2. Wang L, Zhang Y, Liu K, Chen H, Yang R, Ma X, Kim HG, Bode AM, Kim DJ, Dong Z. Oncotarget 9 34200-34212 (2018)
  6. Computational and Biochemical Discovery of RSK2 as a Novel Target for Epigallocatechin Gallate (EGCG). Chen H, Yao K, Chang X, Shim JH, Kim HG, Malakhova M, Kim DJ, Bode AM, Dong Z. PLoS One 10 e0130049 (2015)
  7. A non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host. Alexa A, Sok P, Gross F, Albert K, Kobori E, Póti ÁL, Gógl G, Bento I, Kuang E, Taylor SS, Zhu F, Ciliberto A, Reményi A. Nat Commun 13 472 (2022)
  8. 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)
  9. 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)
  10. C─H⋯O hydrogen bonds in kinase-inhibitor interfaces. Derewenda ZS, Hawro I, Derewenda U. IUBMB Life 72 1233-1242 (2020)
  11. A flexible data-free framework for structure-based de novo drug design with reinforcement learning. Du H, Jiang D, Zhang O, Wu Z, Gao J, Zhang X, Wang X, Deng Y, Kang Y, Li D, Pan P, Hsieh CY, Hou T. Chem Sci 14 12166-12181 (2023)


Reviews citing this publication (2)

  1. Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores. Gógl G, Kornev AP, Reményi A, Taylor SS. Trends Biochem Sci 44 300-311 (2019)
  2. Signal transduction and molecular targets of selected flavonoids. Bode AM, Dong Z. Antioxid Redox Signal 19 163-180 (2013)

Articles citing this publication (11)

  1. Myricetin inhibits proliferation and induces apoptosis and cell cycle arrest in gastric cancer cells. Feng J, Chen X, Wang Y, Du Y, Sun Q, Zang W, Zhao G. Mol Cell Biochem 408 163-170 (2015)
  2. The Structure of an NDR/LATS Kinase-Mob Complex Reveals a Novel Kinase-Coactivator System and Substrate Docking Mechanism. Gógl G, Schneider KD, Yeh BJ, Alam N, Nguyen Ba AN, Moses AM, Hetényi C, Reményi A, Weiss EL. PLoS Biol 13 e1002146 (2015)
  3. 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)
  4. Myricetin exerts anti-proliferative, anti-invasive, and pro-apoptotic effects on esophageal carcinoma EC9706 and KYSE30 cells via RSK2. Zang W, Wang T, Wang Y, Li M, Xuan X, Ma Y, Du Y, Liu K, Dong Z, Zhao G. Tumour Biol 35 12583-12592 (2014)
  5. A Rising Cancer Prevention Target of RSK2 in Human Skin Cancer. Arul N, Cho YY. Front Oncol 3 201 (2013)
  6. The promise and challenges of targeting RSK for the treatment of cancer. Stratford AL, Dunn SE. Expert Opin Ther Targets 15 1-4 (2011)
  7. RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth. Yao K, Peng C, Zhang Y, Zykova TA, Lee MH, Lee SY, Rao E, Chen H, Ryu J, Wang L, Zhang Y, Gao G, He W, Ma WY, Liu K, Bode AM, Dong Z, Li B, Dong Z. Proc Natl Acad Sci U S A 114 12791-12796 (2017)
  8. Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer. Chrysostomou S, Roy R, Prischi F, Thamlikitkul L, Chapman KL, Mufti U, Peach R, Ding L, Hancock D, Moore C, Molina-Arcas M, Mauri F, Pinato DJ, Abrahams JM, Ottaviani S, Castellano L, Giamas G, Pascoe J, Moonamale D, Pirrie S, Gaunt C, Billingham L, Steven NM, Cullen M, Hrouda D, Winkler M, Post J, Cohen P, Salpeter SJ, Bar V, Zundelevich A, Golan S, Leibovici D, Lara R, Klug DR, Yaliraki SN, Barahona M, Wang Y, Downward J, Skehel JM, Ali MMU, Seckl MJ, Pardo OE. Sci Transl Med 13 eaba4627 (2021)
  9. MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy. Robinson EL, Drawnel FM, Mehdi S, Archer CR, Liu W, Okkenhaug H, Alkass K, Aronsen JM, Nagaraju CK, Sjaastad I, Sipido KR, Bergmann O, Arthur JSC, Wang X, Roderick HL. Cells 11 604 (2022)
  10. Activation of RSK by phosphomimetic substitution in the activation loop is prevented by structural constraints. Somale D, Di Nardo G, di Blasio L, Puliafito A, Vara-Messler M, Chiaverina G, Palmiero M, Monica V, Gilardi G, Primo L, Gagliardi PA. Sci Rep 10 591 (2020)
  11. 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)


Quick links