Binding modes of a new epoxysuccinyl-peptide inhibitor of cysteine proteases. Where and how do cysteine proteases express their selectivity?
Papain from Carica papaya, an easily available cysteine protease, is the best-studied representative of this family of enzymes. The three dimensional structure of papain is very similar to that of other cysteine proteases of either plant (actinidin, caricain, papaya protease IV) or animal (cathepsins B, K, L, H) origin. As abnormalities in the activities of mammalian cysteine proteases accompany a variety of diseases, there has been a long-lasting interest in the development of potent and selective inhibitors for these enzymes. A covalent inhibitor of cysteine proteases, designed as a combination of epoxysuccinyl and peptide moieties, has been modeled in the catalytic pocket of papain. A number of its configurations have been generated and relaxed by constrained simulated annealing-molecular dynamics in water. A clear conformational variability of this inhibitor is discussed in the context of a conspicuous conformational diversity observed earlier in several solid-state structures of other complexes between cysteine proteases and covalent inhibitors. The catalytic pockets S2 and even more so S3, as defined by the pioneering studies on the papain-ZPACK, papain-E64c and papain-leupeptin complexes, appear elusive in view of the evident flexibility of the present inhibitor and in confrontation with the obvious conformational scatter seen in other examples. This predicts limited chances for the development of selective structure-based inhibitors of thiol proteases, designed to exploit the minute differences in the catalytic pockets of various members of this family. A simultaneous comparison of the three published proenzyme structures suggests the enzyme's prosegment binding loop-prosegment interface as a new potential target for selective inhibitors of papain-related thiol proteases.
Czaplewski
C
C
Faculty of Chemistry, University of Gdańsk, ul. Sobieskiego 18, 80-952, Gdańsk, Poland.
Grzonka
Z
Z
Jaskólski
M
M
Kasprzykowski
F
F
Kozak
M
M
Politowska
E
E
Ciarkowski
J
J
D000595:Amino Acid Sequence; D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D004792:Enzyme Precursors / Q000737:chemistry; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D010206:Papain / Q000737:chemistry; D016415:Sequence Alignment; D013379:Substrate Specificity; D013696:Temperature; D014867:Water / Q000737:chemistry
D015853:Cysteine Proteinase Inhibitors; D004792:Enzyme Precursors; D004852:Epoxy Compounds; C119893:Inh1 cysteine protease inhibitor; D009842:Oligopeptides; D014867:Water; D003546:Cysteine Endopeptidases; D010206:Papain