1mrv › Citations

Crystal structure of an inactive Akt2 kinase domain.

Huang X, Begley M, Morgenstern KA, Gu Y, Rose P, Zhao H, Zhu X
Structure 11 21-30 (2003)
Cited: 84 times
EuropePMC logo PMID: 12517337

Abstract

Akt/PKB represents a subfamily of three isoforms from the AGC serine/threonine kinase family. Amplification of Akt activity has been implicated in diseases that involve inappropriate cell survival, including a number of human malignancies. The structure of an inactive and unliganded Akt2 kinase domain reveals several features that distinguish it from other kinases. Most of the alpha helix C is disordered. The activation loop in this structure adopts a conformation that appears to sterically hinder the binding of both ATP and peptide substrate. In addition, an intramolecular disulfide bond is observed between two cysteines in the activation loop. Residues within the linker region between the N- and C-terminal lobes also contribute to the inactive conformation by partially occupying the ATP binding site.

Reviews - 1mrv mentioned but not cited (3)

  1. Substrate and docking interactions in serine/threonine protein kinases. Goldsmith EJ, Akella R, Min X, Zhou T, Humphreys JM. Chem Rev 107 5065-5081 (2007)
  2. Protein Kinase Targets in Breast Cancer. García-Aranda M, Redondo M. Int J Mol Sci 18 E2543 (2017)
  3. Computer-Aided Identification of Kinase-Targeted Small Molecules for Cancer: A Review on AKT Protein. Primavera E, Palazzotti D, Barreca ML, Astolfi A. Pharmaceuticals (Basel) 16 993 (2023)

Articles - 1mrv mentioned but not cited (6)

  1. Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. Wu WI, Voegtli WC, Sturgis HL, Dizon FP, Vigers GP, Brandhuber BJ. PLoS One 5 e12913 (2010)
  2. Conformational changes in redox pairs of protein structures. Fan SW, George RA, Haworth NL, Feng LL, Liu JY, Wouters MA. Protein Sci 18 1745-1765 (2009)
  3. Highly precise protein-protein interaction prediction based on consensus between template-based and de novo docking methods. Ohue M, Matsuzaki Y, Shimoda T, Ishida T, Akiyama Y. BMC Proc 7 S6 (2013)
  4. Effects of ethanol on conformational changes of Akt studied by chemical cross-linking, mass spectrometry, and (18)O labeling. Huang BX, Kim HY. ACS Chem Biol 7 387-394 (2012)
  5. ProSelection: A Novel Algorithm to Select Proper Protein Structure Subsets for in Silico Target Identification and Drug Discovery Research. Wang N, Wang L, Xie XQ. J Chem Inf Model 57 2686-2698 (2017)
  6. Strategy toward Kinase-Selective Drug Discovery. Zhang M, Liu Y, Jang H, Nussinov R. J Chem Theory Comput 19 1615-1628 (2023)


Reviews citing this publication (20)

  1. Regulation of protein kinases; controlling activity through activation segment conformation. Nolen B, Taylor S, Ghosh G. Mol Cell 15 661-675 (2004)
  2. Redox regulation of protein kinases. Corcoran A, Cotter TG. FEBS J 280 1944-1965 (2013)
  3. Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Wang K, Zhang T, Dong Q, Nice EC, Huang C, Wei Y. Cell Death Dis 4 e537 (2013)
  4. AKT crystal structure and AKT-specific inhibitors. Kumar CC, Madison V. Oncogene 24 7493-7501 (2005)
  5. The redox regulation of PI 3-kinase-dependent signaling. Leslie NR. Antioxid Redox Signal 8 1765-1774 (2006)
  6. Redox regulation of epidermal growth factor receptor signaling through cysteine oxidation. Truong TH, Carroll KS. Biochemistry 51 9954-9965 (2012)
  7. PDK2: the missing piece in the receptor tyrosine kinase signaling pathway puzzle. Dong LQ, Liu F. Am J Physiol Endocrinol Metab 289 E187-96 (2005)
  8. Redox regulation of protein kinases. Truong TH, Carroll KS. Crit Rev Biochem Mol Biol 48 332-356 (2013)
  9. Forkhead box o as a sensor, mediator, and regulator of redox signaling. de Keizer PL, Burgering BM, Dansen TB. Antioxid Redox Signal 14 1093-1106 (2011)
  10. Redox features of the cell: a gender perspective. Malorni W, Campesi I, Straface E, Vella S, Franconi F. Antioxid Redox Signal 9 1779-1801 (2007)
  11. The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance. Weng MS, Chang JH, Hung WY, Yang YC, Chien MH. J Exp Clin Cancer Res 37 61 (2018)
  12. Lining the pockets of kinases and phosphatases. Gold MG, Barford D, Komander D. Curr Opin Struct Biol 16 693-701 (2006)
  13. The Hallmarks of Cancer from a Redox Perspective. Hornsveld M, Dansen TB. Antioxid Redox Signal 25 300-325 (2016)
  14. Integrating opposing signals toward Forkhead box O. van den Berg MC, Burgering BM. Antioxid Redox Signal 14 607-621 (2011)
  15. Redox regulation of the insulin signalling pathway. Lennicke C, Cochemé HM. Redox Biol 42 101964 (2021)
  16. Redox regulation of cancer metastasis: molecular signaling and therapeutic opportunities. Yang W, Zou L, Huang C, Lei Y. Drug Dev Res 75 331-341 (2014)
  17. Redox Homeostasis in Pancreatic β-Cells: From Development to Failure. Benáková Š, Holendová B, Plecitá-Hlavatá L. Antioxidants (Basel) 10 526 (2021)
  18. Integration of phosphoproteomic, chemical, and biological strategies for the functional analysis of targeted protein phosphorylation. Guo M, Huang BX. Proteomics 13 424-437 (2013)
  19. Protein cooperation: from neurons to networks. Volonté C, D'Ambrosi N, Amadio S. Prog Neurobiol 86 61-71 (2008)
  20. Serum and glucocorticoid-regulated kinase 1: Structure, biological functions, and its inhibitors. Jang H, Park Y, Jang J. Front Pharmacol 13 1036844 (2022)

Articles citing this publication (55)

  1. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Li CW, Lim SO, Xia W, Lee HH, Chan LC, Kuo CW, Khoo KH, Chang SS, Cha JH, Kim T, Hsu JL, Wu Y, Hsu JM, Yamaguchi H, Ding Q, Wang Y, Yao J, Lee CC, Wu HJ, Sahin AA, Allison JP, Yu D, Hortobagyi GN, Hung MC. Nat Commun 7 12632 (2016)
  2. mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. Hresko RC, Mueckler M. J Biol Chem 280 40406-40416 (2005)
  3. PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Brognard J, Sierecki E, Gao T, Newton AC. Mol Cell 25 917-931 (2007)
  4. Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo. Calleja V, Alcor D, Laguerre M, Park J, Vojnovic B, Hemmings BA, Downward J, Parker PJ, Larijani B. PLoS Biol 5 e95 (2007)
  5. A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles. Wang C, Weerapana E, Blewett MM, Cravatt BF. Nat Methods 11 79-85 (2014)
  6. PKC maturation is promoted by nucleotide pocket occupation independently of intrinsic kinase activity. Cameron AJ, Escribano C, Saurin AT, Kostelecky B, Parker PJ. Nat Struct Mol Biol 16 624-630 (2009)
  7. Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Hindie V, Stroba A, Zhang H, Lopez-Garcia LA, Idrissova L, Zeuzem S, Hirschberg D, Schaeffer F, Jørgensen TJ, Engel M, Alzari PM, Biondi RM. Nat Chem Biol 5 758-764 (2009)
  8. 17Beta-estradiol protects against oxidative stress-induced cell death through the glutathione/glutaredoxin-dependent redox regulation of Akt in myocardiac H9c2 cells. Urata Y, Ihara Y, Murata H, Goto S, Koji T, Yodoi J, Inoue S, Kondo T. J Biol Chem 281 13092-13102 (2006)
  9. Allosteric activation of the protein kinase PDK1 with low molecular weight compounds. Engel M, Hindie V, Lopez-Garcia LA, Stroba A, Schaeffer F, Adrian I, Imig J, Idrissova L, Nastainczyk W, Zeuzem S, Alzari PM, Hartmann RW, Piiper A, Biondi RM. EMBO J 25 5469-5480 (2006)
  10. Downregulation of catalase by reactive oxygen species via PI 3 kinase/Akt signaling in mesangial cells. Venkatesan B, Mahimainathan L, Das F, Ghosh-Choudhury N, Ghosh Choudhury G. J Cell Physiol 211 457-467 (2007)
  11. Structural basis for the regulation of protein kinase A by activation loop phosphorylation. Steichen JM, Kuchinskas M, Keshwani MM, Yang J, Adams JA, Taylor SS. J Biol Chem 287 14672-14680 (2012)
  12. Global consequences of activation loop phosphorylation on protein kinase A. Steichen JM, Iyer GH, Li S, Saldanha SA, Deal MS, Woods VL, Taylor SS. J Biol Chem 285 3825-3832 (2010)
  13. Potential role of glutathione in evolution of thiol-based redox signaling sites in proteins. Mohanasundaram KA, Haworth NL, Grover MP, Crowley TM, Goscinski A, Wouters MA. Front Pharmacol 6 1 (2015)
  14. Global redox proteome and phosphoproteome analysis reveals redox switch in Akt. Su Z, Burchfield JG, Yang P, Humphrey SJ, Yang G, Francis D, Yasmin S, Shin SY, Norris DM, Kearney AL, Astore MA, Scavuzzo J, Fisher-Wellman KH, Wang QP, Parker BL, Neely GG, Vafaee F, Chiu J, Yeo R, Hogg PJ, Fazakerley DJ, Nguyen LK, Kuyucak S, James DE. Nat Commun 10 5486 (2019)
  15. Cigarette Smoke Disrupted Lung Endothelial Barrier Integrity and Increased Susceptibility to Acute Lung Injury via Histone Deacetylase 6. Borgas D, Chambers E, Newton J, Ko J, Rivera S, Rounds S, Lu Q. Am J Respir Cell Mol Biol 54 683-696 (2016)
  16. Akt Cys-310-targeted inhibition by hydroxylated benzene derivatives is tightly linked to their immunosuppressive effects. Lee JY, Lee YG, Lee J, Yang KJ, Kim AR, Kim JY, Won MH, Park J, Yoo BC, Kim S, Cho WJ, Cho JY. J Biol Chem 285 9932-9948 (2010)
  17. The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein. Smith KJ, Carter PS, Bridges A, Horrocks P, Lewis C, Pettman G, Clarke A, Brown M, Hughes J, Wilkinson M, Bax B, Reith A. Structure 12 1067-1077 (2004)
  18. Interdomain conformational changes in Akt activation revealed by chemical cross-linking and tandem mass spectrometry. Huang BX, Kim HY. Mol Cell Proteomics 5 1045-1053 (2006)
  19. 3-D structure and dynamics of protein kinase B-new mechanism for the allosteric regulation of an AGC kinase. Calleja V, Laguerre M, Larijani B. J Chem Biol 2 11-25 (2009)
  20. Glutaredoxin mediates Akt and eNOS activation by flow in a glutathione reductase-dependent manner. Wang J, Pan S, Berk BC. Arterioscler Thromb Vasc Biol 27 1283-1288 (2007)
  21. Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt. Durgadoss L, Nidadavolu P, Valli RK, Saeed U, Mishra M, Seth P, Ravindranath V. FASEB J 26 1473-1483 (2012)
  22. Molecular alterations in apoptotic pathways after PKB/Akt-mediated chemoresistance in NCI H460 cells. Hövelmann S, Beckers TL, Schmidt M. Br J Cancer 90 2370-2377 (2004)
  23. Crystal structure of the kinase domain of serum and glucocorticoid-regulated kinase 1 in complex with AMP PNP. Zhao B, Lehr R, Smallwood AM, Ho TF, Maley K, Randall T, Head MS, Koretke KK, Schnackenberg CG. Protein Sci 16 2761-2769 (2007)
  24. 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)
  25. Differential thiol oxidation of the signaling proteins Akt, PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle. Tan PL, Shavlakadze T, Grounds MD, Arthur PG. Int J Biochem Cell Biol 62 72-79 (2015)
  26. InterAKTions with FKBPs--mutational and pharmacological exploration. Fabian AK, März A, Neimanis S, Biondi RM, Kozany C, Hausch F. PLoS One 8 e57508 (2013)
  27. Structural bases of PAS domain-regulated kinase (PASK) activation in the absence of activation loop phosphorylation. Kikani CK, Antonysamy SA, Bonanno JB, Romero R, Zhang FF, Russell M, Gheyi T, Iizuka M, Emtage S, Sauder JM, Turk BE, Burley SK, Rutter J. J Biol Chem 285 41034-41043 (2010)
  28. Differential activation of CREB by Akt1 and Akt2. Kato S, Ding J, Du K. Biochem Biophys Res Commun 354 1061-1066 (2007)
  29. Homo-oligomerization and activation of AMP-activated protein kinase are mediated by the kinase domain alphaG-helix. Scholz R, Suter M, Weimann T, Polge C, Konarev PV, Thali RF, Tuerk RD, Viollet B, Wallimann T, Schlattner U, Neumann D. J Biol Chem 284 27425-27437 (2009)
  30. Heterotetrameric sarcosine oxidase: structure of a diflavin metalloenzyme at 1.85 A resolution. Chen ZW, Hassan-Abdulah A, Zhao G, Jorns MS, Mathews FS. J Mol Biol 360 1000-1018 (2006)
  31. Regulation of the interaction between protein kinase C-related protein kinase 2 (PRK2) and its upstream kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1). Dettori R, Sonzogni S, Meyer L, Lopez-Garcia LA, Morrice NA, Zeuzem S, Engel M, Piiper A, Neimanis S, Frödin M, Biondi RM. J Biol Chem 284 30318-30327 (2009)
  32. 4-benzimidazolyl-3-phenylbutanoic acids as novel PIF-pocket-targeting allosteric inhibitors of protein kinase PKCζ. Fröhner W, Lopez-Garcia LA, Neimanis S, Weber N, Navratil J, Maurer F, Stroba A, Zhang H, Biondi RM, Engel M. J Med Chem 54 6714-6723 (2011)
  33. AKT Degradation Selectively Inhibits the Growth of PI3K/PTEN Pathway-Mutant Cancers with Wild-Type KRAS and BRAF by Destabilizing Aurora Kinase B. Xu J, Yu X, Martin TC, Bansal A, Cheung K, Lubin A, Stratikopoulos E, Cahuzac KM, Wang L, Xie L, Zhou R, Shen Y, Wu X, Yao S, Qiao R, Poulikakos PI, Chen X, Liu J, Jin J, Parsons R. Cancer Discov 11 3064-3089 (2021)
  34. Extracellular adenosine triphosphate protects oxidative stress-induced increase of p21(WAF1/Cip1) and p27(Kip1) expression in primary cultured renal proximal tubule cells: role of PI3K and Akt signaling. Lee YJ, Lee JH, Han HJ. J Cell Physiol 209 802-810 (2006)
  35. 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)
  36. Inhibition of H2O2-induced cell death through FOXO1 modulation by EUK-172 in SK-N-MC cells. Gheysarzadeh A, Yazdanparast R. Eur J Pharmacol 697 47-52 (2012)
  37. Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses. Kadioglu O, Saeed M, Kuete V, Greten HJ, Efferth T, Efferth T. Front Pharmacol 9 355 (2018)
  38. Nitric oxide activates intradomain disulfide bond formation in the kinase loop of Akt1/PKBα after burn injury. Lu XM, Tompkins RG, Fischman AJ. Int J Mol Med 31 740-750 (2013)
  39. Cellular model system to dissect the isoform-selectivity of Akt inhibitors. Quambusch L, Depta L, Landel I, Lubeck M, Kirschner T, Nabert J, Uhlenbrock N, Weisner J, Kostka M, Levy LM, Schultz-Fademrecht C, Glanemann F, Althoff K, Müller MP, Siveke JT, Rauh D. Nat Commun 12 5297 (2021)
  40. Solution structure of the oncogenic MIEN1 protein reveals a thioredoxin-like fold with a redox-active motif. Hsu CH, Shen TL, Chang CF, Chang YY, Huang LY. PLoS One 7 e52292 (2012)
  41. Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH. Shearn CT, Saba LM, Roede JR, Orlicky DJ, Shearn AH, Petersen DR. Free Radic Biol Med 113 280-290 (2017)
  42. Phenylalanine-Based Inactivator of AKT Kinase: Design, Synthesis, and Biological Evaluation. Nguyen T, Coover RA, Verghese J, Moran RG, Ellis KC. ACS Med Chem Lett 5 462-467 (2014)
  43. Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells. López-Grueso MJ, González R, Muntané J, Bárcena JA, Padilla CA. Antioxidants (Basel) 8 E501 (2019)
  44. Akt2 and p-Akt overexpression in oral cancer cells is due to a reduced rate of protein degradation. Archewa P, Pata S, Chotjumlong P, Supanchart C, Krisanaprakornkit S, Iamaroon A. J Investig Clin Dent 8 (2017)
  45. Bioinformatics-based discovery and characterization of an AKT-selective inhibitor 9-chloro-2-methylellipticinium acetate (CMEP) in breast cancer cells. Zhang M, Fang X, Liu H, Guo R, Wu X, Li B, Zhu F, Ling Y, Griffith BN, Wang S, Yang D. Cancer Lett 252 244-258 (2007)
  46. The Akt isoforms, their unique functions and potential as anticancer therapeutic targets. Santi SA, Douglas AC, Lee H. Biomol Concepts 1 389-401 (2010)
  47. Fine-tuning AKT kinase activity through direct lysine methylation. Guo J, Wei W. Cell Cycle 18 917-922 (2019)
  48. Redox States of Protein Cysteines in Pathways of Protein Turnover and Cytoskeleton Dynamics Are Changed with Aging and Reversed by Slc7a11 Restoration in Mouse Lung Fibroblasts. Zheng Y, Merchant ML, Burke TJ, Ritzenthaler JD, Li M, Gaweda AE, Benz FW, Roman J, Watson WH. Oxid Med Cell Longev 2020 2468986 (2020)
  49. Conformational changes in Akt1 activation probed by amide hydrogen/deuterium exchange and nano-electrospray ionization mass spectrometry. Guo M, Huang BX, Kim HY. Rapid Commun Mass Spectrom 23 1885-1891 (2009)
  50. SILAM for quantitative proteomics of liver Akt1/PKBα after burn injury. Lu XM, Tompkins RG, Fischman AJ. Int J Mol Med 29 461-471 (2012)
  51. AKTs/PKBs: molecular characterization, tissue expression and transcriptional responses to insulin and/or wortmannin in yellow catfish Pelteobagrus fulvidraco. Zhuo MQ, Pan YX, Wu K, Xu YH, Zhang LH, Luo Z. Fish Physiol Biochem 43 719-730 (2017)
  52. Complexity of NAC Action as an Antidiabetic Agent: Opposing Effects of Oxidative and Reductive Stress on Insulin Secretion and Insulin Signaling. Argaev-Frenkel L, Rosenzweig T. Int J Mol Sci 23 2965 (2022)
  53. Molecular docking appraisal of Dysphania ambrosioides phytochemicals as potential inhibitor of a key triple-negative breast cancer driver gene. Anifowose LO, Paimo OK, Adegboyega FN, Ogunyemi OM, Akano RO, Hammad SF, Ghazy MA. In Silico Pharmacol 11 15 (2023)
  54. Structural study of the catalytic domain of PKCzeta using infrared spectroscopy and two-dimensional infrared correlation spectroscopy. Sánchez-Bautista S, Kazaks A, Beaulande M, Torrecillas A, Corbalán-García S, Gómez-Fernández JC. FEBS J 273 3273-3286 (2006)
  55. Structural basis of a redox-dependent conformational switch that regulates the stress kinase p38α. Pous J, Baginski B, Martin-Malpartida P, González L, Scarpa M, Aragon E, Ruiz L, Mees RA, Iglesias-Fernández J, Orozco M, Nebreda AR, Macias MJ. Nat Commun 14 7920 (2023)


Quick links