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Crystal structures of trypanosoma brucei oligopeptidase B broaden the paradigm of catalytic regulation in prolyl oligopeptidase family enzymes
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Canning, Peter, Rea, Dean, Morty, Rory E. and Fülöp, Vilmos (2013) Crystal structures of trypanosoma brucei oligopeptidase B broaden the paradigm of catalytic regulation in prolyl oligopeptidase family enzymes. PLoS One, Volume 8 (Number 11). Article number e79349. doi:10.1371/journal.pone.0079349 ISSN 1932-6203.
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WRAP_Fulop_journal.pone.0079349.pdf - Published Version Available under License Creative Commons Attribution. Download (984Kb) | Preview |
Official URL: http://dx.doi.org/10.1371/journal.pone.0079349
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.
| Item Type: | Journal Article | ||||
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| Subjects: | Q Science > QD Chemistry R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
| Library of Congress Subject Headings (LCSH): | Trypanosoma brucei , Enzymes | ||||
| Journal or Publication Title: | PLoS One | ||||
| Publisher: | Public Library of Science | ||||
| ISSN: | 1932-6203 | ||||
| Official Date: | 12 November 2013 | ||||
| Dates: |
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| Volume: | Volume 8 | ||||
| Number: | Number 11 | ||||
| Page Range: | Article number e79349 | ||||
| DOI: | 10.1371/journal.pone.0079349 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||
| Date of first compliant deposit: | 26 December 2015 | ||||
| Date of first compliant Open Access: | 26 December 2015 | ||||
| Funder: | Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Seventh Framework Programme (European Commission) (FP7) | ||||
| Grant number: | 223077 (FP7) |
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