1u54 Citations

Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1.

J. Biol. Chem. 279 44039-45 (2004)
Related entries: 1u46, 1u4d

Cited: 26 times
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ACK1 is a multidomain non-receptor tyrosine kinase that is an effector of the Cdc42 GTPase. Members of the ACK family have a unique domain ordering and are the only tyrosine kinases known to interact with Cdc42. In contrast with many protein kinases, ACK1 has only a modest increase in activity upon phosphorylation. We have solved the crystal structures of the human ACK1 kinase domain in both the unphosphorylated and phosphorylated states. Comparison of these structures reveals that ACK1 adopts an activated conformation independent of phosphorylation. Furthermore, the unphosphorylated activation loop is structured, and its conformation resembles that seen in activated tyrosine kinases. In addition to the apo structure, complexes are also presented with a non-hydrolyzable nucleotide analog (adenosine 5'-(beta,gamma-methylenetriphosphate)) and with the natural product debromohymenialdisine, a general inhibitor of many protein kinases. Analysis of these structures reveals a typical kinase fold, a pre-organization into the activated conformation, and an unusual substrate-binding cleft.

Articles - 1u54 mentioned but not cited (2)

  1. Incomplete protein packing as a selectivity filter in drug design. Fernández A. Structure 13 1829-1836 (2005)
  2. Packing defects as selectivity switches for drug-based protein inhibitors. Fernández A, Scott R, Berry RS. Proc. Natl. Acad. Sci. U.S.A. 103 323-328 (2006)

Reviews citing this publication (3)

  1. Mechanisms of RET signaling in cancer: current and future implications for targeted therapy. Plaza-Menacho I, Mologni L, McDonald NQ. Cell. Signal. 26 1743-1752 (2014)
  2. ACK1 tyrosine kinase: targeted inhibition to block cancer cell proliferation. Mahajan K, Mahajan NP. Cancer Lett. 338 185-192 (2013)
  3. Shepherding AKT and androgen receptor by Ack1 tyrosine kinase. Mahajan K, Mahajan NP. J. Cell. Physiol. 224 327-333 (2010)

Articles citing this publication (21)

  1. Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange. Oliver AW, Paul A, Boxall KJ, Barrie SE, Aherne GW, Garrett MD, Mittnacht S, Pearl LH. EMBO J. 25 3179-3190 (2006)
  2. Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper. Wang Z, Liu J, Sudom A, Ayres M, Li S, Wesche H, Powers JP, Walker NP. Structure 14 1835-1844 (2006)
  3. Down-regulation of active ACK1 is mediated by association with the E3 ubiquitin ligase Nedd4-2. Chan W, Tian R, Lee YF, Sit ST, Lim L, Manser E. J. Biol. Chem. 284 8185-8194 (2009)
  4. High-throughput kinase profiling: a more efficient approach toward the discovery of new kinase inhibitors. Miduturu CV, Deng X, Kwiatkowski N, Yang W, Brault L, Filippakopoulos P, Chung E, Yang Q, Schwaller J, Knapp S, King RW, Lee JD, Herrgard S, Zarrinkar P, Gray NS. Chem. Biol. 18 868-879 (2011)
  5. Conserved tyrosine kinase promotes the import of silencing RNA into Caenorhabditis elegans cells. Jose AM, Kim YA, Leal-Ekman S, Hunter CP. Proc. Natl. Acad. Sci. U.S.A. 109 14520-14525 (2012)
  6. Constitutive activated Cdc42-associated kinase (Ack) phosphorylation at arrested endocytic clathrin-coated pits of cells that lack dynamin. Shen H, Ferguson SM, Dephoure N, Park R, Yang Y, Volpicelli-Daley L, Gygi S, Schlessinger J, De Camilli P. Mol. Biol. Cell 22 493-502 (2011)
  7. Cancer-associated mutations activate the nonreceptor tyrosine kinase Ack1. Prieto-Echagüe V, Gucwa A, Craddock BP, Brown DA, Miller WT. J. Biol. Chem. 285 10605-10615 (2010)
  8. Conservation, variability and the modeling of active protein kinases. Knight JD, Qian B, Baker D, Kothary R. PLoS ONE 2 e982 (2007)
  9. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. Pao-Chun L, Chan PM, Chan W, Manser E. J. Biol. Chem. 284 34954-34963 (2009)
  10. Regulation of ack-family nonreceptor tyrosine kinases. Prieto-Echagüe V, Miller WT. J Signal Transduct 2011 742372 (2011)
  11. Small-molecule inhibitors binding to protein kinases. Part I: exceptions from the traditional pharmacophore approach of type I inhibition. Backes A, Zech B, Felber B, Klebl B, Müller G. Expert Opin Drug Discov 3 1409-1425 (2008)
  12. Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans. Plaza-Menacho I, Barnouin K, Goodman K, Martínez-Torres RJ, Borg A, Murray-Rust J, Mouilleron S, Knowles P, McDonald NQ. Mol. Cell 53 738-751 (2014)
  13. Synthesis and optimization of substituted furo[2,3-d]-pyrimidin-4-amines and 7H-pyrrolo[2,3-d]pyrimidin-4-amines as ACK1 inhibitors. Jiao X, Kopecky DJ, Liu J, Liu J, Jaen JC, Cardozo MG, Sharma R, Walker N, Wesche H, Li S, Farrelly E, Xiao SH, Wang Z, Kayser F. Bioorg. Med. Chem. Lett. 22 6212-6217 (2012)
  14. Structure-function correlation of G6, a novel small molecule inhibitor of Jak2: indispensability of the stilbenoid core. Majumder A, Govindasamy L, Magis A, Kiss R, Polgár T, Baskin R, Allan RW, Agbandje-McKenna M, Reuther GW, Keseru GM, Bisht KS, Sayeski PP. J. Biol. Chem. 285 31399-31407 (2010)
  15. The Cdc42-associated kinase ACK1 is not autoinhibited but requires Src for activation. Chan W, Sit ST, Manser E. Biochem. J. 435 355-364 (2011)
  16. Ack1: activation and regulation by allostery. Gajiwala KS, Maegley K, Ferre R, He YA, Yu X. PLoS ONE 8 e53994 (2013)
  17. The human kinome and kinase inhibition. Duong-Ly KC, Peterson JR. Curr Protoc Pharmacol Chapter 2 Unit2.9 (2013)
  18. Effects of ligand binding upon flexibility of proteins. Erman B. Proteins 83 805-808 (2015)
  19. Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1. Rudd ML, Mohamed H, Price JC, O'Hara AJ, Le Gallo M, Urick ME, NISC Comparative Sequencing Program, Cruz P, Zhang S, Hansen NF, Godwin AK, Sgroi DC, Wolfsberg TG, Mullikin JC, Merino MJ, Bell DW. BMC Cancer 14 884 (2014)
  20. Overexpression of activated Cdc42-associated kinase1 (Ack1) predicts tumor recurrence and poor survival in human hepatocellular carcinoma. Wang B, Xu T, Liu J, Zang S, Gao L, Huang A. Pathol. Res. Pract. 210 787-792 (2014)
  21. Phosphorylation State-Dependent High Throughput Screening of the c-Met Kinase. Behshad E, Klabe RM, Margulis A, Becker-Pasha M, Rupar MJ, Collier P, Liu PC, Hollis GF, Burn TC, Wynn R. Curr Chem Genomics 4 27-33 (2010)