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Science 13 June 1997:
Vol. 276. no. 5319, pp. 1665 - 1669
DOI: 10.1126/science.276.5319.1665
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Research Articles

Structural Insights into the Evolution of an Antibody Combining Site

Gary J. Wedemayer, Phillip A. Patten, * Leo H. Wang, Peter G. Schultz, dagger Raymond C. Stevens

The crystal structures of a germline antibody Fab fragment and its complex with hapten have been solved at 2.1 Å resolution. These structures are compared with the corresponding crystal structures of the affinity-matured antibody, 48G7, which has a 30,000 times higher affinity for hapten as a result of nine replacement somatic mutations. Significant changes in the configuration of the combining site occur upon binding of hapten to the germline antibody, whereas hapten binds to the mature antibody by a lock-and-key fit mechanism. The reorganization of the combining site that was nucleated by hapten binding is further optimized by somatic mutations that occur up to 15 Å from bound hapten. These results suggest that the binding potential of the primary antibody repertoire may be significantly expanded by the ability of germline antibodies to adopt more than one combining-site configuration, with both antigen binding and somatic mutation stabilizing the configuration with optimal hapten complementarity.

The authors are in the Department of Chemistry, University of California, Berkeley, CA 94720, USA and at the Lawrence Livermore National Laboratory, Berkeley; P. G. Schultz is also with the Howard Hughes Medical Institute.
*   Present address: Maxygen, Inc., 3410 Central Expressway, Santa Clara, CA 94501, USA.

dagger    To whom correspondence should be addressed.

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