Di Carluccio C, Soriano-Maldonado P, Berni F, de Haas CJC, Temming AR, Hendriks A, Ali S, Molinaro A, Silipo A, van Sorge NM, van Raaij MJ, Codee JDC, Marchetti R Antibody Recognition of Different Staphylococcus aureus Wall Teichoic Acid Glycoforms ACS Central Science8(10) (2022)
1383-1392
NCBI PubMed ID:36313161 Publication DOI:10.1021/acscentsci.2c00125 Journal NLM ID:101660035 Publisher: Washington DC: ACS Correspondence: N.M. van Sorge <n.m.vansorgeamsterdamumc.nl>; m.J. van Raaij <mjvanraaijcnb.csic.es>; J.D.C. Codee <jcodeechem.leidenuniv.nl>; R. Marchetti <roberta.marchettiunina.it> Institutions: Department of Chemical Sciences, University of Naples Federico II, via Cinthia 4, 80126 Naples, Italy, Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Calle Darwin 3, 28049 Madrid, Spain, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands, Medical Microbiology, UMC Utrecht, Utrecht University, 3508 Utrecht, The Netherlands, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands, Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam UMC, 1105 AZAmsterdam, The Netherlands
Wall teichoic acids (WTAs) are glycopolymers decorating the surface of Gram-positive bacteria and potential targets for antibody-mediated treatments against Staphylococcus aureus, including methicillin-resistant (MRSA) strains. Through a combination of glycan microarray, synthetic chemistry, crystallography, NMR, and computational studies, we unraveled the molecular and structural details of fully defined synthetic WTA fragments recognized by previously described monoclonal antibodies (mAbs 4461 and 4497). Our results unveiled the structural requirements for the discriminatory recognition of α- and β-GlcNAc-modified WTA glycoforms by the complementarity-determining regions (CDRs) of the heavy and light chains of the mAbs. Both mAbs interacted not only with the sugar moiety but also with the phosphate groups as well as residues in the ribitol phosphate (RboP) units of the WTA backbone, highlighting their significant role in ligand specificity. Using elongated WTA fragments, containing two sugar modifications, we also demonstrated that the internal carbohydrate moiety of α-GlcNAc-modified WTA is preferentially accommodated in the binding pocket of mAb 4461 with respect to the terminal moiety. Our results also explained the recently documented cross-reactivity of mAb 4497 for β-1,3/β-1,4-GlcNAc-modified WTA, revealing that the flexibility of the RboP backbone is crucial to allow positioning of both glycans in the antibody binding pocket.
Methods: 13C NMR, 1H NMR, NMR-2D, chemical synthesis, MD simulations, STD NMR, microarray binding assays, monoclonal antibodies, X-ray crystallography Enzymes that release or process the structure: glycosyltransferases TarM (α-1,4), TarS (β-1,4), TarP (β-1,3) 3D data: 3D data
Di Carluccio C, Soriano-Maldonado P, Berni F, de Haas CJC, Temming AR, Hendriks A, Ali S, Molinaro A, Silipo A, van Sorge NM, van Raaij MJ, Codee JDC, Marchetti R Antibody Recognition of Different Staphylococcus aureus Wall Teichoic Acid Glycoforms ACS Central Science8(10) (2022)
1383-1392
The structure was elucidated in this paper NCBI PubMed ID:36313161 Publication DOI:10.1021/acscentsci.2c00125 Journal NLM ID:101660035 Publisher: Washington DC: ACS Correspondence: N.M. van Sorge <n.m.vansorgeamsterdamumc.nl>; m.J. van Raaij <mjvanraaijcnb.csic.es>; J.D.C. Codee <jcodeechem.leidenuniv.nl>; R. Marchetti <roberta.marchettiunina.it> Institutions: Department of Chemical Sciences, University of Naples Federico II, via Cinthia 4, 80126 Naples, Italy, Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Calle Darwin 3, 28049 Madrid, Spain, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands, Medical Microbiology, UMC Utrecht, Utrecht University, 3508 Utrecht, The Netherlands, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands, Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam UMC, 1105 AZAmsterdam, The Netherlands
Wall teichoic acids (WTAs) are glycopolymers decorating the surface of Gram-positive bacteria and potential targets for antibody-mediated treatments against Staphylococcus aureus, including methicillin-resistant (MRSA) strains. Through a combination of glycan microarray, synthetic chemistry, crystallography, NMR, and computational studies, we unraveled the molecular and structural details of fully defined synthetic WTA fragments recognized by previously described monoclonal antibodies (mAbs 4461 and 4497). Our results unveiled the structural requirements for the discriminatory recognition of α- and β-GlcNAc-modified WTA glycoforms by the complementarity-determining regions (CDRs) of the heavy and light chains of the mAbs. Both mAbs interacted not only with the sugar moiety but also with the phosphate groups as well as residues in the ribitol phosphate (RboP) units of the WTA backbone, highlighting their significant role in ligand specificity. Using elongated WTA fragments, containing two sugar modifications, we also demonstrated that the internal carbohydrate moiety of α-GlcNAc-modified WTA is preferentially accommodated in the binding pocket of mAb 4461 with respect to the terminal moiety. Our results also explained the recently documented cross-reactivity of mAb 4497 for β-1,3/β-1,4-GlcNAc-modified WTA, revealing that the flexibility of the RboP backbone is crucial to allow positioning of both glycans in the antibody binding pocket.
Structure type: fragment of a bigger structure Location inside paper: p. 1384, Fig. 2, table S2, compound 1 Trivial name: WTA Compound class: teichoic acid Contained glycoepitopes:IEDB_114703,IEDB_137340,IEDB_141807,IEDB_151531,IEDB_591403
Methods: 13C NMR, 1H NMR, NMR-2D, chemical synthesis, MD simulations, STD NMR, microarray binding assays, monoclonal antibodies, X-ray crystallography Synthetic data: chemical Comments, role: synthetic glycoform of the S. aureus WTA 3D data: 3D data
Di Carluccio C, Soriano-Maldonado P, Berni F, de Haas CJC, Temming AR, Hendriks A, Ali S, Molinaro A, Silipo A, van Sorge NM, van Raaij MJ, Codee JDC, Marchetti R Antibody Recognition of Different Staphylococcus aureus Wall Teichoic Acid Glycoforms ACS Central Science8(10) (2022)
1383-1392
The structure was elucidated in this paper NCBI PubMed ID:36313161 Publication DOI:10.1021/acscentsci.2c00125 Journal NLM ID:101660035 Publisher: Washington DC: ACS Correspondence: N.M. van Sorge <n.m.vansorgeamsterdamumc.nl>; m.J. van Raaij <mjvanraaijcnb.csic.es>; J.D.C. Codee <jcodeechem.leidenuniv.nl>; R. Marchetti <roberta.marchettiunina.it> Institutions: Department of Chemical Sciences, University of Naples Federico II, via Cinthia 4, 80126 Naples, Italy, Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Calle Darwin 3, 28049 Madrid, Spain, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands, Medical Microbiology, UMC Utrecht, Utrecht University, 3508 Utrecht, The Netherlands, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands, Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam UMC, 1105 AZAmsterdam, The Netherlands
Wall teichoic acids (WTAs) are glycopolymers decorating the surface of Gram-positive bacteria and potential targets for antibody-mediated treatments against Staphylococcus aureus, including methicillin-resistant (MRSA) strains. Through a combination of glycan microarray, synthetic chemistry, crystallography, NMR, and computational studies, we unraveled the molecular and structural details of fully defined synthetic WTA fragments recognized by previously described monoclonal antibodies (mAbs 4461 and 4497). Our results unveiled the structural requirements for the discriminatory recognition of α- and β-GlcNAc-modified WTA glycoforms by the complementarity-determining regions (CDRs) of the heavy and light chains of the mAbs. Both mAbs interacted not only with the sugar moiety but also with the phosphate groups as well as residues in the ribitol phosphate (RboP) units of the WTA backbone, highlighting their significant role in ligand specificity. Using elongated WTA fragments, containing two sugar modifications, we also demonstrated that the internal carbohydrate moiety of α-GlcNAc-modified WTA is preferentially accommodated in the binding pocket of mAb 4461 with respect to the terminal moiety. Our results also explained the recently documented cross-reactivity of mAb 4497 for β-1,3/β-1,4-GlcNAc-modified WTA, revealing that the flexibility of the RboP backbone is crucial to allow positioning of both glycans in the antibody binding pocket.
Methods: 13C NMR, 1H NMR, NMR-2D, chemical synthesis, MD simulations, STD NMR, microarray binding assays, monoclonal antibodies, X-ray crystallography Synthetic data: chemical Comments, role: synthetic glycoform of the S. aureus WTA 3D data: 3D data
Di Carluccio C, Soriano-Maldonado P, Berni F, de Haas CJC, Temming AR, Hendriks A, Ali S, Molinaro A, Silipo A, van Sorge NM, van Raaij MJ, Codee JDC, Marchetti R Antibody Recognition of Different Staphylococcus aureus Wall Teichoic Acid Glycoforms ACS Central Science8(10) (2022)
1383-1392
The structure was elucidated in this paper NCBI PubMed ID:36313161 Publication DOI:10.1021/acscentsci.2c00125 Journal NLM ID:101660035 Publisher: Washington DC: ACS Correspondence: N.M. van Sorge <n.m.vansorgeamsterdamumc.nl>; m.J. van Raaij <mjvanraaijcnb.csic.es>; J.D.C. Codee <jcodeechem.leidenuniv.nl>; R. Marchetti <roberta.marchettiunina.it> Institutions: Department of Chemical Sciences, University of Naples Federico II, via Cinthia 4, 80126 Naples, Italy, Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Calle Darwin 3, 28049 Madrid, Spain, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands, Medical Microbiology, UMC Utrecht, Utrecht University, 3508 Utrecht, The Netherlands, Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands, Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam UMC, 1105 AZAmsterdam, The Netherlands
Wall teichoic acids (WTAs) are glycopolymers decorating the surface of Gram-positive bacteria and potential targets for antibody-mediated treatments against Staphylococcus aureus, including methicillin-resistant (MRSA) strains. Through a combination of glycan microarray, synthetic chemistry, crystallography, NMR, and computational studies, we unraveled the molecular and structural details of fully defined synthetic WTA fragments recognized by previously described monoclonal antibodies (mAbs 4461 and 4497). Our results unveiled the structural requirements for the discriminatory recognition of α- and β-GlcNAc-modified WTA glycoforms by the complementarity-determining regions (CDRs) of the heavy and light chains of the mAbs. Both mAbs interacted not only with the sugar moiety but also with the phosphate groups as well as residues in the ribitol phosphate (RboP) units of the WTA backbone, highlighting their significant role in ligand specificity. Using elongated WTA fragments, containing two sugar modifications, we also demonstrated that the internal carbohydrate moiety of α-GlcNAc-modified WTA is preferentially accommodated in the binding pocket of mAb 4461 with respect to the terminal moiety. Our results also explained the recently documented cross-reactivity of mAb 4497 for β-1,3/β-1,4-GlcNAc-modified WTA, revealing that the flexibility of the RboP backbone is crucial to allow positioning of both glycans in the antibody binding pocket.
Methods: 13C NMR, 1H NMR, NMR-2D, chemical synthesis, MD simulations, STD NMR, microarray binding assays, monoclonal antibodies, X-ray crystallography Synthetic data: chemical Comments, role: synthetic glycoform of the S. aureus WTA 3D data: 3D data
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amsterdamumc.nl>; m.J. van Raaij <mjvanraaij