What comparisons of natural and chimeric contacts reveal about inhibition of human cathepsins K, L and S by their prosegments

  • Juan Carlos Martínez-Hernández Universidad Autónoma Metropolitana-Iztapalapa
  • Iris N. Serratos Universidad Autónoma Metropolitana-Iztapalapa
  • César Millán-Pacheco Universidad Autónoma del Estado de Morelos
  • Arturo Rojo-Domínguez Universidad Autónoma Metropolitana-Cuajimalpa
  • Jaqueline Padilla-Zúñiga Universidad Autónoma Metropolitana-Iztapalapa
Keywords: human cathepsins, cathepsin inhibition, proteinase chimeric complexes, protease prosegments, cysteine proteases

Abstract

Human cathepsins K, L, and S, which are involved in the development of several serious diseases, are strongly inhibited by their related prosegments, to which they are covalently bound or simply forming complexes. In this work, three-dimensional structures of the three natural complexes of these enzymes with their related proregions were constructed, as well as six chimeric complexes of the same three prosegments with their non-cognate enzymes. We made a comparative study of the contacts in all nine structures throughout their active sites. The analysis was performed looking for a structural parameter that could agree with the values of the inhibition constants reported experimentally for each of the nine complexes. We found that this correlating parameter was the difference of the electrostatic energy (involving hydrogen bonds and ion pairs) at the binding interface of a 13-amino acid fragment of the prosegments. We used the results of this work, on the one hand, to identify the key residues involved in the electrostatic intermolecular recognition in each studied complex and, on the other, to explain some results achieved by different research groups on the inhibition of the same enzymes analyzed here. It was found that the natural cathepsin L complex showed a higher number of electrostatic interactions, some of them interconnected, when compared to the other two natural complexes. In addition, the chimeric contacts revealed binding sites that could be used to achieve a more potent inhibition of these cathepsins, avoiding cross-interactions.

Author Biographies

Juan Carlos Martínez-Hernández, Universidad Autónoma Metropolitana-Iztapalapa

Departamento de Química

Área de Biofisicoquímica

Iris N. Serratos, Universidad Autónoma Metropolitana-Iztapalapa

Departamento de Química

Dr.

César Millán-Pacheco, Universidad Autónoma del Estado de Morelos

Facultad de Farmacia

Dr.

Arturo Rojo-Domínguez, Universidad Autónoma Metropolitana-Cuajimalpa

Profesor Titular C

Departamento de Ciencias Naturales

Jaqueline Padilla-Zúñiga, Universidad Autónoma Metropolitana-Iztapalapa

Profesor Titular B

Departamento de Química

Área de Biofisicoquímica

References

Schick, C.; Pemberton, P.A.; Shi, G.P.; Kamachi, Y.; Cataltepe, S.; Bartuski, A.J.; Gornstein, E.R.; Bromme, D.; Chapman, H.A.; Silverman, G.A. Biochem. 1998, 37, 5258-5266.

Palermo, C.; Joyce. J.A. Trends Pharmacol Sci. 2007, 29, 22-28.

Schornberg, K.; Matsuyama, S.; Kabsch, K.; Delos, S.; Bouton, A.; White, J. J. Virol. 2006, 80, 4174-4178.

Lankelma, J.M.; Voorend, D.M.; Barwari, T.; Koetsveld, J.; Van der Spek, A.H.; De Porto, A.P.N.A.; Van Rooijen, G.; Van Noorden, C.J.F. Life Sciences. 2010, 86, 225–233.

Bromme, D.; Klaus, J.L.; Okamoto, K.; Rasnick, D.; Palmer, J.T. Biochem. J. 1996, 315, 85-89.

Cywin, C.L.; Firestone, R.A.; McNeil, D.W.; Grygon, C.A.; Crane, K.M.; White, D.M.; Kinkade, P.R.; Hopkins, J.L.; Davidson, W.; Labadia, M.E.; Wildeson, J.; Morelock, M.M.; Peterson, J.D.; Raymond, E.L.; Brownand, M.L.; Spero, D.M. Bioorg. Med. Chem. 2003, 11, 733-740.

Gauthier, J.Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L.T.; Falgueyret, J.P.; Kimmel, D.B.; Lamontagne, S.; Le´ger, S., Le Riche, T.; Sing, C.; Masse´, L.F.; McKay, D.J.; Nicoll-Griffith, D.A.; Oballa, R.M.; Palmer, J.T.; Percival, M.D.; Riendeau, D.; Robichaud, J.; Rodan, G.A.; Rodan, S.B., Seto, C.; The´rien, M.; Truong, V.L.; Venuti, M.C.; Wesolowski, G.; Young, R.N.; Zambonia, R.; Black, W.C. Bioorg. Med. Chem. Lett. 2008, 18, 923-928.

Stoch, S.A.; Wagner, J.A.Clin. Pharmacol. Ther. 2008, 83, 172-176.

Löser, R.; Pietzsch, J. Cysteine cathepsins. Front Chem. 2015, 23, 3-37.

Kramer, L.; Turk, D.; Turk, B. Trends Pharmacol Sci. 2017, 38, 873-889.

Coulombe, R.; Grochulski, P.; Sivaraman, J.; Ménard, R.; Morton, J.S. Cygler, M. EMBO J. 1996, 15, 5492-5503.

Maubach, G.; Schilling, K.; Rommerskirch, W.; Wenz, I.; Schultz, J.E.; Weber, E.; Wiederanders, B. Eur. J. Biochem. 1997, 250, 745-750.

Billington, C.J.; Mason, P.; Magny, M.C.; Mort, J.S. Biochem. Biophys. Res. Commun. 2000, 276, 924-929.

Nomura, T.; Fujisawa, Y. Biochem. Biophys. Res. Commun. 1997, 230, 143-146.

Ishidoh, K.; Saido, T.C.; Kawashima, S.; Hirose, M.; Watanabe, S.; Sato, N.; Kominami, E. Biochem. Biophys. Res. Commun. 1998, 252, 202-207.

Ménard, R.; Carmona, E.; Takebe, S.; Dufour, E.; Plouffe, C.; Mason, P.; Mort, J.S. J. Biol. Chem. 1998, 273, 4478-4484.

Rieman, D.J.; McClung, H.A.; Dodds, R.A.; Hwang, S.M.; Holmes, M.W.; James, I.E.; Drake, F.H.; Gowen, M. Bone. 2001, 28, 282-289.

Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. Nucleic Acids Res. 2000, 28, 235-242.

Schechter, I.; Berger, A. Biochem. Biophys. Res. Commun. 1967, 27, 157-162.

Turk, V.; Stoka, V.; Vasiljeva, O.; Renko, M.; Sun, T.; Turk, B.; Turk, D. Biochim. Biophys. Acta. 2012, 1824, 68-88.

Guay, J.; Falgueyret, J.P.; Ducret, A.; Percival, M.D.; Mancini, J.A. Eur. J. Biochim. 2000, 267, 6311-6318.

Wiederanders, B. Acta. Biochim. Pol. 2003, 50, 691.

Ang, K.K.H.; Ratnam, J.; Gut, J.; Legac J.; Hansell, E.; Mackey, Z.B.; Skrzypczynska, K.M.; Debnath, A.; Engel, J.C.; Rosenthal, P.J.; McKerrow, J.H.; Arkin, M.R. and Renslo, A.R. PLoSNegl. Trop. Dis. 2011, 5, e1023, doi:10.1371/journal.pntd.0001023.

Sosic, I.; Mirkovic, B.; Arenz, K.; Stefane, B.; Kos, J. and Gobec, S. J. Med. Chem. 2012, 56, 521-533.

Molecular Operating Environment (MOE), 2013.08; Chemical Computing Group ULC, 1010 Sherbrooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2018.

Gasteiger, J.; Marsili, M. Tetrahedron. 1980, 36, 3219-3228.

Londe, J.M.L.; Zhao, B.; Janson, C.A.; D'Alessio, K.J.; McQueney, M.S.; Orsini, M.J.; Debouck, C.M.; Smith, W.W. Biochem. 1999, 19. 862-869.

Cygler, M.; Coulombe, R. Crystal structure of procathepsin L doi: 102210/pdb1CS8/pdb.

Kaulmann, G.; Palm, G.J.; Schilling, K.; Hilgenfeld, R.; Wiederanders, B. Protein Sci. 2006, 15; 2619-2629.

Nucleic Acids Research, Volume 45, Issue D1, 4 January 2017, Pages D158–D169,https://doi.org/10.1093/nar/gkw1099.

Inaoka, T.; Bilbe, G.; Ishibashi, O.; Tezuka, K.; Kumegawa, M.; Kokubo, T. Biochem. Biophys. Res. Commun. 1995, 206, 89-96.

Gal, S.; Gottesman, M.M. Biochem. J. 1988, 253, 303-306.

Shi, G.P. Munger, J.S.; Meara, J.P.; Rich, D.H.; Chapman, H.A. J. Biol. Chem. 1992, 267, 7258-7262.

Söding, J.; Biegert, A.; Lupas, A.N. Nucleic Acids Res. 2005, 33, 244-248.

Eisenberg, D.; Lüthy, R.; Bowie, J.U. Methods Enzymol. 1997, 277, 396-404.

Laskowski,R.A.; MacArthur, M.W.; Moss, D.S.; Thornton, J.M. J. Appl. Cryst. 1993, 26, 283-291.

Laskowski, R. A.Nucleic Acids Res. 2009, 37, D355–D359.

Li, C.S.; Deschenes, D.; Desmarais, S.; Falgueyret, J.P.; Gauthier, J.Y.; Kimmel, D.B.; Léger, S.; Massé, F.; McGrath, M.E.; McKay, D.J.; Percival, M.D.; Riendeau, D.; Rodan, S.B.; Thérien, M.; Truong, V.L.; Wesolowski, G.; Zamboni, R.; Black, W.C. Bioorg. Med. Chem. Lett. 2006, 16, 1985-1989.

Chowdhury, S.F.; Sivaraman, J.; Wang, J.; Devanathan, G.; Lachance, P.; Qi, H.; Ménard, R.; Lefebvre, J.; Konishi, Y.; Cygler, M.; Sulea, T.; Purisima, E.O. J. Med. Chem. 2002, 45, 5321-5329.

Wiener, D.K.; Lee-Dutra, A.; Bembenek, S.; Nguyen, S.; Thurmond, R.L.; Sun, S.; Karlsson, L.; Grice, C.A.; Jones, T.K.; Edwards, J.P. Bioorg. Med. Chem. Lett. 2010, 20, 2379-2382.

Baker, N.A.; Sept, D.; Joseph, S.; Holst, M.J.; McCammon, J.A. Proc. Natl. Acad. Sci. 2001, 98, 10037-10041.

Carmona, E.; Dufour, E.; Plouffe, C.; Takebe, S.; Mason, P.; Mort, J.S.; Ménard, R. Biochem. 1996, 35,8149-8157.

Cappetta, M.; Roth, I.; Díaz, A.; Tort, J.; Roche, L. Biol. Chem. 2002, 383, 1215-122.

Published
01-10-2019