Crystal structure of Leishmania major oligopeptidase B gives insight into the enzymatic properties of a trypanosomatid virulence factor

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dc.contributor.author McLuskey, K en
dc.contributor.author Paterson, Neil en
dc.contributor.author Bland, ND en
dc.contributor.author Isaacs, NW en
dc.contributor.author Mottram, JC en
dc.date.accessioned 2012-03-12T19:08:00Z en
dc.date.issued 2010 en
dc.identifier.citation Journal of biological chemistry 285(50):39249-39259 2010 en
dc.identifier.issn 0021-9258 en
dc.identifier.uri http://hdl.handle.net/2292/13947 en
dc.description.abstract Oligopeptidase B (OPB) is a serine peptidase with dibasic substrate specificity. It is found in bacteria, plants, and trypanosomatid pathogens, where it has been identified as a virulence factor and potential drug target. In this study we expressed active recombinant Leishmania major OPB and provide the first structure of an oligopeptidase B at high resolution. The crystallographic study reveals that OPB comprises two domains, a catalytic and a propeller domain, linked together by a hinge region. The structure has been determined in complex with the oligopeptide, protease-inhibitor antipain, giving detailed information on the enzyme active site and extended substrate binding pockets. It shows that Glu-621 plays a critical role in the S1 binding pocket and, along with Phe-603, is largely responsible for the enzyme substrate specificity in P1. In the S2 binding pocket, Tyr-499 was shown to be important for substrate stability. The structure also allowed an investigation into the function of residues highlighted in other studies including Glu-623, which was predicted to be involved in the S1 binding pocket but is found forming an inter-domain hydrogen bond. Additional important salt bridges/hydrogen bonds between the two domains were observed, highlighting the significance of the domain interface in OPB. This work provides a foundation for the study of the role of OPBs as virulence factors in trypanosomatids. It could facilitate the development of specific OPB inhibitors with therapeutic potential by exploiting its unique substrate recognition properties as well as providing a model for OPBs in general. en
dc.publisher The American Society for Biochemistry and Molecular Biology, Inc. en
dc.relation.ispartofseries Journal of Biological Chemistry en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0021-9258/ en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.subject Leishmania major -- metabolism; Serine Endopeptidases -- chemistry; Trypanosoma -- metabolism en
dc.title Crystal structure of Leishmania major oligopeptidase B gives insight into the enzymatic properties of a trypanosomatid virulence factor en
dc.type Journal Article en
dc.identifier.doi 10.1074/jbc.M110.156679 en
pubs.issue 50 en
pubs.begin-page 39249 en
pubs.volume 285 en
dc.rights.holder Copyright: The American Society for Biochemistry and Molecular Biology, Inc. en
pubs.end-page 39259 en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Article en
pubs.elements-id 206467 en
pubs.record-created-at-source-date 2011-02-24 en


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