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dc.contributor.authorTrastoy, Beatriz
dc.contributor.authorLomino, Joseph V.
dc.contributor.authorPierce, Brian G.
dc.contributor.authorCarter, Lester G.
dc.contributor.authorGunther, Sebastian
dc.contributor.authorGiddens, John P.
dc.contributor.authorSnyder, Greg A.
dc.contributor.authorWeiss, Thomas M.
dc.contributor.authorWeng, Zhiping
dc.contributor.authorWang, Lai-Xi
dc.contributor.authorSundberg, Eric J.
dc.date2022-08-11T08:07:59.000
dc.date.accessioned2022-08-23T15:38:19Z
dc.date.available2022-08-23T15:38:19Z
dc.date.issued2014-05-06
dc.date.submitted2015-06-24
dc.identifier.citationProc Natl Acad Sci U S A. 2014 May 6;111(18):6714-9. doi: 10.1073/pnas.1322908111. Epub 2014 Apr 21. <a href="http://dx.doi.org/10.1073/pnas.1322908111">Link to article on publisher's site</a>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.1322908111
dc.identifier.pmid24753590
dc.identifier.urihttp://hdl.handle.net/20.500.14038/25913
dc.description.abstractTo evade host immune mechanisms, many bacteria secrete immunomodulatory enzymes. Streptococcus pyogenes, one of the most common human pathogens, secretes a large endoglycosidase, EndoS, which removes carbohydrates in a highly specific manner from IgG antibodies. This modification renders antibodies incapable of eliciting host effector functions through either complement or Fc gamma receptors, providing the bacteria with a survival advantage. On account of this antibody-specific modifying activity, EndoS is being developed as a promising injectable therapeutic for autoimmune diseases that rely on autoantibodies. Additionally, EndoS is a key enzyme used in the chemoenzymatic synthesis of homogenously glycosylated antibodies with tailored Fc gamma receptor-mediated effector functions. Despite the tremendous utility of this enzyme, the molecular basis of EndoS specificity for, and processing of, IgG antibodies has remained poorly understood. Here, we report the X-ray crystal structure of EndoS and provide a model of its encounter complex with its substrate, the IgG1 Fc domain. We show that EndoS is composed of five distinct protein domains, including glycosidase, leucine-rich repeat, hybrid Ig, carbohydrate binding module, and three-helix bundle domains, arranged in a distinctive V-shaped conformation. Our data suggest that the substrate enters the concave interior of the enzyme structure, is held in place by the carbohydrate binding module, and that concerted conformational changes in both enzyme and substrate are required for subsequent antibody deglycosylation. The EndoS structure presented here provides a framework from which novel endoglycosidases could be engineered for additional clinical and biotechnological applications.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=24753590&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020096/
dc.subjectBacterial Proteins
dc.subjectCatalytic Domain
dc.subjectCrystallography, X-Ray
dc.subjectGlycoside Hydrolases
dc.subjectHumans
dc.subjectImmunoglobulin Fc Fragments
dc.subjectImmunoglobulin G
dc.subjectImmunologic Factors
dc.subjectModels, Molecular
dc.subjectProtein Conformation
dc.subjectProtein Structure, Tertiary
dc.subjectScattering, Small Angle
dc.subjectStreptococcus pyogenes
dc.subjectSubstrate Specificity
dc.subjectX-Ray Diffraction
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectBioinformatics
dc.subjectComputational Biology
dc.subjectIntegrative Biology
dc.subjectSystems Biology
dc.titleCrystal structure of Streptococcus pyogenes EndoS, an immunomodulatory endoglycosidase specific for human IgG antibodies
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume111
dc.source.issue18
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1058&amp;context=bioinformatics_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/bioinformatics_pubs/54
dc.identifier.contextkey7256013
refterms.dateFOA2022-08-23T15:38:20Z
html.description.abstract<p>To evade host immune mechanisms, many bacteria secrete immunomodulatory enzymes. Streptococcus pyogenes, one of the most common human pathogens, secretes a large endoglycosidase, EndoS, which removes carbohydrates in a highly specific manner from IgG antibodies. This modification renders antibodies incapable of eliciting host effector functions through either complement or Fc gamma receptors, providing the bacteria with a survival advantage. On account of this antibody-specific modifying activity, EndoS is being developed as a promising injectable therapeutic for autoimmune diseases that rely on autoantibodies. Additionally, EndoS is a key enzyme used in the chemoenzymatic synthesis of homogenously glycosylated antibodies with tailored Fc gamma receptor-mediated effector functions. Despite the tremendous utility of this enzyme, the molecular basis of EndoS specificity for, and processing of, IgG antibodies has remained poorly understood. Here, we report the X-ray crystal structure of EndoS and provide a model of its encounter complex with its substrate, the IgG1 Fc domain. We show that EndoS is composed of five distinct protein domains, including glycosidase, leucine-rich repeat, hybrid Ig, carbohydrate binding module, and three-helix bundle domains, arranged in a distinctive V-shaped conformation. Our data suggest that the substrate enters the concave interior of the enzyme structure, is held in place by the carbohydrate binding module, and that concerted conformational changes in both enzyme and substrate are required for subsequent antibody deglycosylation. The EndoS structure presented here provides a framework from which novel endoglycosidases could be engineered for additional clinical and biotechnological applications.</p>
dc.identifier.submissionpathbioinformatics_pubs/54
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.source.pages6714-9


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