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Glycobiology Advance Access published online on September 18, 2009
Glycobiology, doi:10.1093/glycob/cwp150
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

The role of CDR H3 in Antibody Recognition of a Synthetic Analogue of a Lipopolysaccharide Antigen

Cory L Brooks1,*, Ryan J Blackler1,*, Georg Sixta2, Paul Kosma2, Sven Müller-Loennies3, Lore Brade3, Tomoko Hirama4, C. Roger MacKenzie4, Helmut Brade3,{dagger} and Stephen V Evans1,{ddagger}

1 University of Victoria, Department of Biochemistry and Microbiology, Victoria, BC, V8P 3P6 Canada
2 Department of Chemistry, University of Natural Resources and Applied Life Sciences, A-1190 Vienna, Austria
3 Research Center Borstel, Leibniz Center for Medicine and Biosciences, Parkallee 22, D-23845 Borstel, Germany
4 Institute for Biological Sciences, National Research Council Canada, Ottawa, Ontario K1A 0R6, Canada

{dagger} Address correspondence to: Helmut Brade Research Center Borstel, Leibniz Center for Medicine and Biosciences, Parkallee 22, D-23845 Borstel, Germany. FAX: 04537 - 188 - 419; E-mail: hebra{at}fz-borstel.de

{ddagger} Address correspondence to: Stephen V. Evans, University of Victoria, Department of Biochemistry and Microbiology, PO Box 3055 STN CSC, Victoria, BC, Canada, V8P 3P6. FAX: 250-721-8855; E-mail svevans{at}uvic.ca

Received on August 11, 2009; accepted on September 15, 2009

In order to explore the structural basis for adaptability in near germline monoclonal antibodies (mAb), we have examined the specificity of the promiscuous mAb S67-27 to both naturally derived carbohydrate antigens and a variety of synthetic non-natural antigens based on the bacterial lipopolysaccharide component 3-deoxy-{alpha}-D-manno-oct-2-ulosonic acid (Kdo). One such analogue, a 7-O-methyl (7-O-Me) Kdo disaccharide, was found to bind to the antibody with at least 30 fold higher affinity than any other antigen tested. The structure of S67-27 in complex with this analogue and three other naturally occurring Kdo antigens revealed that the enhanced affinity of the mAb for the synthetic analogue was accomplished by the strategic positioning of CDR H3 away from a conserved Kdo binding pocket that allowed the formation of new antibody-antigen contacts. Furthermore, comparison of this structure with the structures of related mAbs revealed how the position and structure of CDR H3 influence the specificity or promiscuity of near-germline carbohydrate-recognizing antibodies by altering the architecture of the combining site.

* These authors contributed equally to this work.


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