Structural insights into the evolution of an antibody combining site

被引:471
作者
Wedemayer, GJ
Patten, PA
Wang, LH
Schultz, PG
Stevens, RC
机构
[1] UNIV CALIF BERKELEY,DEPT CHEM,BERKELEY,CA 94720
[2] UNIV CALIF LAWRENCE LIVERMORE NATL LAB,LIVERMORE,CA 94550
[3] HOWARD HUGHES MED INST,SEATTLE,WA
关键词
D O I
10.1126/science.276.5319.1665
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The crystal structures of a germline antibody Fab fragment and its complex with hapten have been solved at 2.1 Angstrom 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 Angstrom 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.
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页码:1665 / 1669
页数:5
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