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Key role of a structural water molecule for the specificity of 14F7 - An antitumor antibody targeting the NeuGc GM3 ganglioside

dc.contributor.authorBjerregaard-Andersen K
dc.contributor.authorAbraha F
dc.contributor.authorJohannesen H
dc.contributor.authorOscarson S
dc.contributor.authorMoreno E
dc.contributor.authorKrengel U.
dc.date.accessioned2022-09-14T14:33:51Z
dc.date.available2022-09-14T14:33:51Z
dc.date.created2021
dc.identifier.issn9596658
dc.identifier.urihttp://hdl.handle.net/11407/7502
dc.descriptionTumor-associated glycolipids such as NeuGc GM3 are auspicious molecular targets in antineoplastic therapies and vaccine strategies. 14F7 is a monoclonal IgG1 with high clinical potential in cancer immunotherapy as it displays extraordinary specificity for NeuGc GM3, while it does not recognize the very similar, ubiquitous NeuAc GM3. Here we present the 2.3 Å crystal structure of the 14F7 antigen-binding domain (14F7 scFv) in complex with the NeuGc GM3 trisaccharide. Modeling analysis and previous mutagenesis data suggest that 14F7 may also bind to an alternative NeuGc GM3 conformation, not observed in the crystal structure. The most intriguing finding, however, was that a water molecule centrally placed in the complementarity-determining region directly mediates the specificity of 14F7 to NeuGc GM3. This has profound impact on the complexity of engineering in the binding site and provides an excellent example of the importance in understanding the water structure in antibody-antigen interactions. © 2021 The Author(s) 2021. Published by Oxford University Press.eng
dc.language.isoeng
dc.publisherOxford University Press
dc.relation.isversionofhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85125121145&doi=10.1093%2fglycob%2fcwab076&partnerID=40&md5=8dff4f59934144ae9223d584da733a63
dc.sourceGlycobiology
dc.titleKey role of a structural water molecule for the specificity of 14F7 - An antitumor antibody targeting the NeuGc GM3 ganglioside
dc.typeArticle
dc.rights.accessrightsinfo:eu-repo/semantics/restrictedAccess
dc.publisher.programCiencias Básicas
dc.type.spaArtículo
dc.identifier.doi10.1093/glycob/cwab076
dc.subject.keywordCarbohydrate-antibody interactionseng
dc.subject.keywordN-glycolyl GM3eng
dc.subject.keywordProtein-carbohydrate interactionseng
dc.subject.keywordWater-mediated antibody specificityeng
dc.subject.keywordWater-mediated interactioneng
dc.subject.keywordX-ray crystal structureeng
dc.relation.citationvolume31
dc.relation.citationissue11
dc.relation.citationstartpage1500
dc.relation.citationendpage1509
dc.publisher.facultyFacultad de Ciencias Básicas
dc.affiliationBjerregaard-Andersen, K., Department of Chemistry, University of Oslo, Oslo, NO-0315, Norway, H. Lundbeck A/S, Valby, Denmark
dc.affiliationAbraha, F., School of Chemistry, University College Dublin, Belfield, Dublin, Ireland, Recipharm OT Chemistry, Uppsala, Sweden
dc.affiliationJohannesen, H., Department of Chemistry, University of Oslo, Oslo, NO-0315, Norway, Department of Biosciences, University of Oslo, Oslo, NO-0316, Norway
dc.affiliationOscarson, S., School of Chemistry, University College Dublin, Belfield, Dublin, Ireland
dc.affiliationMoreno, E., Department of Chemistry, University of Oslo, Oslo, NO-0315, Norway, Facultad de Ciencias Básicas, Universidad de Medellín, Medellín, 050026, Colombia
dc.affiliationKrengel, U., Department of Chemistry, University of Oslo, Oslo, NO-0315, Norway
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dc.identifier.instnameinstname:Universidad de Medellín


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