Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 402, Issue 1, Pages 217-229Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2010.07.027
Keywords
antibody sequence diversity; binary phage library; HER2; receptor oligomer; X-ray structure
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Funding
- Office of Biological and Environmental Research (Department of Energy)
- National Institute of General Medical Sciences (National Institutes of Health)
- National Center for Research Resources, Biomedical Technology Program (National Institutes of Health)
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Engineered antibody paratopes with limited sequence diversity permit assessment of the roles played by different amino acid side chains in creating the high-affinity, high-specificity interactions characteristic of antibodies. We describe a paratope raised against the human ErbB family member HER2, using a binary diversity tryptophan/serine library displayed on phage. Fab37 binds to the extracellular domain of HER2 with sub-nanomolar affinity. An X-ray structure at 3.2 angstrom resolution reveals a contact paratope composed almost entirely of tryptophan and serine residues. Mutagenesis experiments reveal which of these side chains are more important for direct antigen interactions and which are more important for conformational flexibility. The crystal lattice contains an unprecedented trimeric arrangement of HER2 closely related to previously observed homodimers of the related epidermal growth factor receptor. (C) 2010 Elsevier Ltd. All rights reserved.
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