Abstract
Oligopeptidase B cleaves after basic amino acids in peptides up to 30 residues. As a virulence factor in bacteria and trypanosomatid pathogens that is absent in higher eukaryotes, this is a promising drug target. Here we present ligand-free open state and inhibitor-bound closed state crystal structures of oligopeptidase B from Trypanosoma brucei, the causative agent of African sleeping sickness. These (and related) structures show the importance of structural dynamics, governed by a fine enthalpic and entropic balance, in substrate size selectivity and catalysis. Peptides over 30 residues cannot fit the enzyme cavity, preventing the complete domain closure required for a key propeller Asp/Glu to fix the catalytic His and Arg in the catalytically competent conformation. This size exclusion mechanism protects larger peptides and proteins from degradation. Similar bacterial prolyl endopeptidase and archael acylaminoacyl peptidase structures demonstrate this mechanism is conserved among oligopeptidase family enzymes across all three domains of life.
Highlights
African sleeping sickness is a neglected disease affecting 60 million people in sub-Saharan Africa [1]
We have determined crystal structures of T. brucei OPB in the ligand-free open state and antipain-bound closed state. These results provide important information for OPB inhibitor development, and broaden our understanding of the role of structural dynamics in the mechanism of catalytic regulation in PREP family enzymes
Crystal structures were determined in the ligand-free open state and inhibitor-bound closed state at resolution 2.4 and 2.85 A, respectively (Table 1)
Summary
African sleeping sickness (or human African trypanosomiasis) is a neglected disease affecting 60 million people in sub-Saharan Africa [1]. The only currently available drugs are highly toxic [2,3,4] but the disease is fatal if left untreated. This disease, caused by the protozoan parasite Trypanosoma brucei and spread by the bite of the tsetse fly [5], has proliferated across central and western Africa as the Trypanosoma brucei gambiense subspecies, and across eastern and southern Africa as the Trypanosoma brucei rhodesiense form. Chagas disease affects around 11 million people in poorer parts of central and southern America, and is fatal if left untreated
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