Immunological origins of binding and catalysis in a Diels-Alderase antibody.
The three-dimensional structure of an antibody (39-A11) that catalyzes a Diels-Alder reaction has been determined. The structure suggests that the antibody catalyzes this pericyclic reaction through a combination of packing and hydrogen-bonding interactions that control the relative geometries of the bound substrates and electronic distribution in the dienophile. A single somatic mutation, serine-91 of the light chain to valine, is largely responsible for the increase in affinity and catalytic activity of the affinity-matured antibody. Structural and functional studies of the germ-line precursor suggest that 39-A11 and related antibodies derive from a family of germ-line genes that have been selected throughout evolution for the ability of the encoded proteins to form a polyspecific combining site. Germ line-encoded antibodies of this type, which can rapidly evolve into high-affinity receptors for a broad range of structures, may help to expand the binding potential associated with the structural diversity of the primary antibody repertoire.
Romesberg
F E
FE
Howard Hughes Medical Institute and the Department of Chemistry, University of California, Berkeley, CA 94720, USA. 94720, USA.
Spiller
B
B
Schultz
P G
PG
Stevens
R C
RC
D000595:Amino Acid Sequence; D000906:Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017151:Antibodies, Catalytic / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000915:Antibody Affinity; D000918:Antibody Specificity; D001665:Binding Sites; D001666:Binding Sites, Antibody; D002384:Catalysis; D002625:Chemistry, Organic; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D018095:Germ-Line Mutation; D006241:Haptens / Q000276:immunology; D006860:Hydrogen Bonding; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D055601:Organic Chemistry Phenomena; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D000906:Antibodies; D017151:Antibodies, Catalytic; D006241:Haptens; D007140:Immunoglobulin Fab Fragments; D011994:Recombinant Proteins