1bqi Citations

Use of papain as a model for the structure-based design of cathepsin K inhibitors: crystal structures of two papain-inhibitor complexes demonstrate binding to S'-subsites.

Abstract

Papain has been used as a surrogate enzyme in a drug design effort to obtain potent and selective inhibitors of cathepsin K, a new member of the papain superfamily of cysteine proteases that is selectively and highly expressed in osteoclasts and is implicated in bone resorption. Here we report the crystal structures of two papain-inhibitor complexes and the rational design of novel cathepsin K inhibitors. Unlike previously known crystal structures of papain-inhibitor complexes, our papain structures show ligand binding extending deep within the S'-subsites. The two inhibitor complexes, carbobenzyloxyleucinyl-leucinyl-leucinal and carbobenzyloxy-L-leucinyl-L-leucinyl methoxymethyl ketone, were refined to 2.2- and 2.5-A resolution with R-factors of 0.190 and 0. 217, respectively. The S'-subsite interactions with the inhibitors are dominated by an aromatic-aromatic stacking and an oxygen-aromatic ring edge interaction. The knowledge of S'-subsite interactions led to a design strategy for an inhibitor spanning both subsites and yielded a novel, symmetric inhibitor selective for cathepsin K. Simultaneous exploitation of both S- and S'-sites provides a general strategy for the design of cysteine protease inhibitors having high specificity to their target enzymes.

Articles - 1bqi mentioned but not cited (1)

  1. High-resolution complex of papain with remnants of a cysteine protease inhibitor derived from Trypanosoma brucei. Alphey MS, Hunter WN. Acta Crystallogr Sect F Struct Biol Cryst Commun 62 504-508 (2006)


Reviews citing this publication (1)

  1. Structure determinants defining the specificity of papain-like cysteine proteases. Petushkova AI, Savvateeva LV, Zamyatnin AA. Comput Struct Biotechnol J 20 6552-6569 (2022)

Articles citing this publication (23)

  1. Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain. Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H. Cell 104 781-790 (2001)
  2. Development of alpha-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease. Choe Y, Brinen LS, Price MS, Engel JC, Lange M, Grisostomi C, Weston SG, Pallai PV, Cheng H, Hardy LW, Hartsough DS, McMakin M, Tilton RF, Baldino CM, Craik CS. Bioorg Med Chem 13 2141-2156 (2005)
  3. Kinetic characterization and molecular docking of a novel, potent, and selective slow-binding inhibitor of human cathepsin L. Shah PP, Myers MC, Beavers MP, Purvis JE, Jing H, Grieser HJ, Sharlow ER, Napper AD, Huryn DM, Cooperman BS, Smith AB, Diamond SL. Mol Pharmacol 74 34-41 (2008)
  4. Immune-independent and label-free fluorescent assay for Cystatin C detection based on protein-stabilized Au nanoclusters. Lin H, Li L, Lei C, Xu X, Nie Z, Guo M, Huang Y, Yao S. Biosens Bioelectron 41 256-261 (2013)
  5. Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L. Costanzi E, Kuzikov M, Esposito F, Albani S, Demitri N, Giabbai B, Camasta M, Tramontano E, Rossetti G, Zaliani A, Storici P. Int J Mol Sci 22 11779 (2021)
  6. Inhibition of cathepsin B by Au(I) complexes: a kinetic and computational study. Gunatilleke SS, de Oliveira CA, McCammon JA, Barrios AM. J Biol Inorg Chem 13 555-561 (2008)
  7. Reaction mechanism of caspases: insights from QM/MM Car-Parrinello simulations. Sulpizi M, Laio A, VandeVondele J, Cattaneo A, Rothlisberger U, Carloni P. Proteins 52 212-224 (2003)
  8. The mechanism of papain inhibition by peptidyl aldehydes. Shokhen M, Khazanov N, Albeck A. Proteins 79 975-985 (2011)
  9. AutoMatch: target-binding protein design and enzyme design by automatic pinpointing potential active sites in available protein scaffolds. Zhang C, Lai L. Proteins 80 1078-1094 (2012)
  10. Molecular docking of cathepsin L inhibitors in the binding site of papain. Beavers MP, Myers MC, Shah PP, Purvis JE, Diamond SL, Cooperman BS, Huryn DM, Smith AB. J Chem Inf Model 48 1464-1472 (2008)
  11. Fluorescent Probes for Studying Thioamide Positional Effects on Proteolysis Reveal Insight into Resistance to Cysteine Proteases. Liu C, Barrett TM, Chen X, Ferrie JJ, Petersson EJ. Chembiochem 20 2059-2062 (2019)
  12. Conserved water-mediated H-bonding dynamics of catalytic His159 and Asp158: insight into a possible acid-base coupled mechanism in plant thiol protease. Nandi TK, Bairagya HR, Mukhopadhyay BP, Mallik P, Sukul D, Bera AK. J Mol Model 18 2633-2644 (2012)
  13. Proteasome inhibitors enhance bacteriophage lambda (lambda) mediated gene transfer in mammalian cells. Volcy K, Dewhurst S. Virology 384 77-87 (2009)
  14. Rational design of thioamide peptides as selective inhibitors of cysteine protease cathepsin L. Phan HAT, Giannakoulias SG, Barrett TM, Liu C, Petersson EJ. Chem Sci 12 10825-10835 (2021)
  15. Structure-function relationship of Chikungunya nsP2 protease: A comparative study with papain. Ramakrishnan C, Kutumbarao NHV, Suhitha S, Velmurugan D. Chem Biol Drug Des 89 772-782 (2017)
  16. 3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K. Pan X, Tan N, Zeng G, Han H, Huang H. Bioorg Med Chem 14 2771-2778 (2006)
  17. Conserved water-mediated H-bonding dynamics of catalytic Asn 175 in plant thiol protease. Nandi TK, Bairagya HR, Mukhopadhyay BP, Sekar K, Sukul D, Bera AK. J Biosci 34 27-34 (2009)
  18. Quantifying tetrahedral adduct formation and stabilization in the cysteine and the serine proteases. Cleary JA, Doherty W, Evans P, Malthouse JP. Biochim Biophys Acta 1854 1382-1391 (2015)
  19. Crystal structure of the Agrobacterium tumefaciens type VI effector-immunity complex. Fukuhara S, Nakane T, Yamashita K, Ishii R, Ishitani R, Nureki O. Acta Crystallogr F Struct Biol Commun 74 810-816 (2018)
  20. Inhibition of Saccharomyces cerevisiae phosphomannose isomerase by the NO-donor S-nitroso-acetyl-penicillamine. Salvati L, Mattu M, Tiberi F, Polticelli F, Ascenzi P. J Enzyme Inhib 16 287-292 (2001)
  21. Perfluorinated Probes for Noncovalent Protein Recognition and Isolation. Bassanini I, Galli C, Ferrandi EE, Vallone F, Andolfo A, Romeo S. Bioconjug Chem 31 513-519 (2020)
  22. Self Organizing Map-Based Classification of Cathepsin k and S Inhibitors with Different Selectivity Profiles Using Different Structural Molecular Fingerprints: Design and Application for Discovery of Novel Hits. Ihmaid SK, Ahmed HE, Zayed MF, Abadleh MM. Molecules 21 175 (2016)
  23. Identifying and characterizing the biological targets of metallotherapeutics: Two approaches using Au(I)-protein interactions as model systems. Karver MR, Barrios AM. Anal Biochem 382 63-65 (2008)