1f5k › Citations

Crystals of the urokinase type plasminogen activator variant beta(c)-uPAin complex with small molecule inhibitors open the way towards structure-based drug design.

Zeslawska E, Schweinitz A, Karcher A, Sondermann P, Sperl S, Stürzebecher J, Jacob U
J Mol Biol 301 465-75 (2000)
Related entries: 1f5l, 1f92

Cited: 32 times
EuropePMC logo PMID: 10926521

Abstract

Urokinase is a serine protease involved in cancer growth and metastasis. Here we present the first urokinase crystal structure in complex with reversible inhibitors at 2.1 and 2.6 A resolution. These inhibitor complex structures have been obtained from crystals of engineered urokinase type plasminogen activator designed to obtain a crystal form open for inhibitor soaking. The mutant C122S loses its flexible A-chain upon activation cleavage and crystallizes in the presence of benzamidine, which was later displaced by the desired inhibitor. This new soakable crystal form turned out to be of great value in the process of structure-based drug design. The evaluated binding mode of amiloride, and UKI-1D revealed a new subsite of the primary specificity pocket of urokinase that will be employed in the future ligand optimisation process.

Articles - 1f5k mentioned but not cited (1)

  1. High Impact: The Role of Promiscuous Binding Sites in Polypharmacology. Cerisier N, Petitjean M, Regad L, Bayard Q, Réau M, Badel A, Camproux AC. Molecules 24 (2019)


Reviews citing this publication (7)

  1. Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? Matthews H, Ranson M, Kelso MJ. Int J Cancer 129 2051-2061 (2011)
  2. Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours. Muehlenweg B, Sperl S, Magdolen V, Schmitt M, Harbeck N. Expert Opin Biol Ther 1 683-691 (2001)
  3. The plasminogen activation system in periodontal tissue (Review). Wyganowska-Świątkowska M, Surdacka A, Skrzypczak-Jankun E, Jankun J. Int J Mol Med 33 763-768 (2014)
  4. Viral targets of acylguanidines. Gazina EV, Petrou S. Drug Discov Today 17 1039-1043 (2012)
  5. Can components of the plasminogen activation system predict the outcome of kidney transplants? Jankun J, Khan OA, Mostafa HI, Sindhwani P, Skrzypczak-Jankun E. Cent Eur J Immunol 43 222-230 (2018)
  6. Fibrinolysis: an illustrated review. Risman RA, Kirby NC, Bannish BE, Hudson NE, Tutwiler V. Res Pract Thromb Haemost 7 100081 (2023)
  7. Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity. El Salamouni NS, Buckley BJ, Ranson M, Kelso MJ, Yu H. Biophys Rev 14 277-301 (2022)

Articles citing this publication (24)

  1. Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents. Schweinitz A, Steinmetzer T, Banke IJ, Arlt MJ, Stürzebecher A, Schuster O, Geissler A, Giersiefen H, Zeslawska E, Jacob U, Krüger A, Stürzebecher J. J Biol Chem 279 33613-33622 (2004)
  2. Engineering inhibitors highly selective for the S1 sites of Ser190 trypsin-like serine protease drug targets. Katz BA, Sprengeler PA, Luong C, Verner E, Elrod K, Kirtley M, Janc J, Spencer JR, Breitenbucher JG, Hui H, McGee D, Allen D, Martelli A, Mackman RL. Chem Biol 8 1107-1121 (2001)
  3. Gain-of-function mutations in the MEC-4 DEG/ENaC sensory mechanotransduction channel alter gating and drug blockade. Brown AL, Fernandez-Illescas SM, Liao Z, Goodman MB. J Gen Physiol 129 161-173 (2007)
  4. Structural basis of specificity of a peptidyl urokinase inhibitor, upain-1. Zhao G, Yuan C, Wind T, Huang Z, Andreasen PA, Huang M. J Struct Biol 160 1-10 (2007)
  5. Crystal structure of the catalytic domain of DESC1, a new member of the type II transmembrane serine proteinase family. Kyrieleis OJ, Huber R, Ong E, Oehler R, Hunter M, Madison EL, Jacob U. FEBS J 274 2148-2160 (2007)
  6. On the interaction between amiloride and its putative alpha-subunit epithelial Na+ channel binding site. Kashlan OB, Sheng S, Kleyman TR. J Biol Chem 280 26206-26215 (2005)
  7. Synthesis of thiophene-2-carboxamidines containing 2-aminothiazoles and their biological evaluation as urokinase inhibitors. Wilson KJ, Illig CR, Subasinghe N, Hoffman JB, Rudolph MJ, Soll R, Molloy CJ, Bone R, Green D, Randall T, Zhang M, Lewandowski FA, Zhou Z, Sharp C, Maguire D, Grasberger B, DesJarlais RL, Spurlino J. Bioorg Med Chem Lett 11 915-918 (2001)
  8. Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA). Katz BA, Luong C, Ho JD, Somoza JR, Gjerstad E, Tang J, Williams SR, Verner E, Mackman RL, Young WB, Sprengeler PA, Chan H, Mortara K, Janc JW, McGrath ME. J Mol Biol 344 527-547 (2004)
  9. Comparative binding energy analysis for binding affinity and target selectivity prediction. Henrich S, Feierberg I, Wang T, Blomberg N, Wade RC. Proteins 78 135-153 (2010)
  10. Crystals of urokinase type plasminogen activator complexes reveal the binding mode of peptidomimetic inhibitors. Zeslawska E, Jacob U, Schweinitz A, Coombs G, Bode W, Madison E. J Mol Biol 328 109-118 (2003)
  11. Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines. Barber CG, Dickinson RP, Fish PV. Bioorg Med Chem Lett 14 3227-3230 (2004)
  12. 6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease. Buckley BJ, Majed H, Aboelela A, Minaei E, Jiang L, Fildes K, Cheung CY, Johnson D, Bachovchin D, Cook GM, Huang M, Ranson M, Kelso MJ. Bioorg Med Chem Lett 29 126753 (2019)
  13. (R)-3-Amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode. Mueller MM, Sperl S, Stürzebecher J, Bode W, Moroder L. Biol Chem 383 1185-1191 (2002)
  14. 6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer. Buckley BJ, Aboelela A, Minaei E, Jiang LX, Xu Z, Ali U, Fildes K, Cheung CY, Cook SM, Johnson DC, Bachovchin DA, Cook GM, Apte M, Huang M, Ranson M, Kelso MJ. J Med Chem 61 8299-8320 (2018)
  15. Selection and characterization of camelid nanobodies towards urokinase-type plasminogen activator. Kaczmarek JZ, Skottrup PD. Mol Immunol 65 384-390 (2015)
  16. The crystal structures of 3-TAPAP in complexes with the urokinase-type plasminogen activator and picrate. Zesławska E, Jacob U, Stürzebecher J, Oleksyn BJ. Bioorg Med Chem Lett 16 228-234 (2006)
  17. Geometry of GPPE binding to picrate and to the urokinase type plasminogen activator. Zesławska E, Stürzebecher J, Oleksyn BJ. Bioorg Med Chem Lett 17 6212-6215 (2007)
  18. Is inhibition process better described with MD(QM/MM) simulations? The case of urokinase type plasminogen activator inhibitors. Barbault F, Maurel F. J Comput Chem 33 607-616 (2012)
  19. Discovery of TMPRSS2 Inhibitors from Virtual Screening as a Potential Treatment of COVID-19. Hu X, Shrimp JH, Guo H, Xu M, Chen CZ, Zhu W, Zakharov AV, Jain S, Shinn P, Simeonov A, Hall MD, Shen M. ACS Pharmacol Transl Sci 4 1124-1135 (2021)
  20. 3-Amidinophenylalanine-derived matriptase inhibitors can modulate hepcidin production in vitro. Pászti-Gere E, Szombath G, Gütschow M, Steinmetzer T, Székács A. Naunyn Schmiedebergs Arch Pharmacol 393 511-520 (2020)
  21. Synthesis and activity of amides of tripeptides as potential urokinase inhibitors. Markowska A, Bruzgo I, Midura-Nowaczek K. J Enzyme Inhib Med Chem 25 139-142 (2010)
  22. Mutagenesis at Pro309 of single-chain urokinase-type plasminogen activator alters its catalytic properties. Sun Z, Liu JN. Proteins 61 870-877 (2005)
  23. Development of a Mammalian suspension culture for expression of active recombinant human urokinase-type plasminogen activator. Atkins E, Zamora S, Candia BJ, Baca A, Orlando RA. Cytotechnology 49 25-37 (2005)
  24. Structure of an affinity-matured inhibitory recombinant fab against urokinase plasminogen activator reveals basis of potency and specificity. Sevillano N, Bohn MF, Zimanyi M, Chen Y, Petzold C, Gupta S, Ralston CY, Craik CS. Biochim Biophys Acta Proteins Proteom 1869 140562 (2021)


Quick links