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Glycobiology Advance Access originally published online on September 18, 2009
Glycobiology 2010 20(2):138-147; 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 analog of a lipopolysaccharide antigen

Cory L Brooks2,3, Ryan J Blackler2,3, Georg Sixta4, Paul Kosma4, Sven Müller-Loennies5, Lore Brade5, Tomoko Hirama6, C Roger MacKenzie6, Helmut Brade1,5 and Stephen V Evans1,3

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

1 To whom correspondence should be addressed: Tel: +49 (0) 4537-188-474; Fax: 04537-188-419; e-mail: hebra{at}fz-borstel.de and Tel: +250-472-4548; Fax: 250-721-8855; e-mail: svevans{at}uvic.ca

Received on August 11, 2009; revised on September 14, 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 nonnatural antigens based on the bacterial lipopolysaccharide component 3-deoxy-{alpha}-D-manno-oct-2-ulosonic acid (Kdo). One such analog, 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 analog and three other naturally occurring Kdo antigens revealed that the enhanced affinity of the mAb for the synthetic analog 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, the 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.

Key words: antibody structure / Chlamydia / Kdo / protein-carbohydrate interactions

2 These authors contributed equally to this work.


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