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dc.contributor.authorHenningham, Anna
dc.contributor.authorEricsson, Daniel J
dc.contributor.authorLanger, Karla
dc.contributor.authorCasey, Lachlan W
dc.contributor.authorJovcevski, Blagojce
dc.contributor.authorChhatwal, G Singh
dc.contributor.authorAquilina, J Andrew
dc.contributor.authorBatzloff, Michael R
dc.contributor.authorKobe, Bostjan
dc.contributor.authorWalker, Mark J
dc.date.accessioned2017-10-03T00:42:50Z
dc.date.available2017-10-03T00:42:50Z
dc.date.issued2013
dc.date.modified2014-07-28T06:49:12Z
dc.identifier.issn2150-7511
dc.identifier.doi10.1128/mBio.00509-13
dc.identifier.urihttp://hdl.handle.net/10072/56112
dc.description.abstractStreptococcus pyogenes (group A Streptococcus [GAS]) causes ~700 million human infections/year, resulting in >500,000 deaths. There is no commercial GAS vaccine available. The GAS surface protein arginine deiminase (ADI) protects mice against a lethal challenge. ADI is an enzyme that converts arginine to citrulline and ammonia. Administration of a GAS vaccine preparation containing wild-type ADI, a protein with inherent enzymatic activity, may present a safety risk. In an approach intended to maximize the vaccine safety of GAS ADI, X-ray crystallography and structural immunogenic epitope mapping were used to inform vaccine design. This study aimed to knock out ADI enzyme activity without disrupting the three-dimensional structure or the recognition of immunogenic epitopes. We determined the crystal structure of ADI at 2.5 Šresolution and used it to select a number of amino acid residues for mutagenesis to alanine (D166, E220, H275, D277, and C401). Each mutant protein displayed abrogated activity, and three of the mutant proteins (those with the D166A, H275A, and D277A mutations) possessed a secondary structure and oligomerization state equivalent to those of the wild type, produced high-titer antisera, and avoided disruption of B-cell epitopes of ADI. In addition, antisera raised against the D166A and D277A mutant proteins bound to the GAS cell surface. The inactivated D166A and D277A mutant ADIs are ideal for inclusion in a GAS vaccine preparation. There is no human ortholog of ADI, and we confirm that despite limited structural similarity in the active-site region to human peptidyl ADI 4 (PAD4), ADI does not functionally mimic PAD4 and antiserum raised against GAS ADI does not recognize human PAD4.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.format.extent3018279 bytes
dc.format.mimetypeapplication/pdf
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society for Microbiology
dc.publisher.placeUnited States
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrome00509-13-1
dc.relation.ispartofpagetoe00509-13-9
dc.relation.ispartofissue4
dc.relation.ispartofjournalmBio
dc.relation.ispartofvolume4
dc.rights.retentionY
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchBacteriology
dc.subject.fieldofresearchMedical bacteriology
dc.subject.fieldofresearchcode3107
dc.subject.fieldofresearchcode310701
dc.subject.fieldofresearchcode320701
dc.titleStructure-Informed Design of an Enzymatically Inactive Vaccine Component for Group A Streptococcus
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc-sa/3.0/
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2013 Henningham et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
gro.date.issued2013
gro.hasfulltextFull Text
gro.griffith.authorBatzloff, Michael R.


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