title: Structural plasticity and the evolution of antibody affinity and specificity.
abstract: The germline precursor to the ferrochelatase antibody 7G12 was found to bind the polyether jeffamine in addition to its cognate hapten N-methylmesoporphyrin. A comparison of the X-ray crystal structures of the ligand-free germline Fab and its complex with either hapten or jeffamine reveals that the germline antibody undergoes significant conformational changes upon the binding of these two structurally distinct ligands, which lead to increased antibody-ligand complementarity. The five somatic mutations introduced during affinity maturation lead to enhanced binding affinity for hapten and a loss in affinity for jeffamine. Moreover, a comparison of the crystal structures of the germline and affinity-matured antibodies reveals that somatic mutations not only fix the optimal binding site conformation for the hapten, but also introduce interactions that interfere with the binding of non-hapten molecules. The structural plasticity of this germline antibody and the structural effects of the somatic mutations that result in enhanced affinity and specificity for hapten likely represent general mechanisms used by the immune response, and perhaps primitive proteins, to evolve high affinity, selective receptors for so many distinct chemical structures.
authors.affiliation: Department of Chemistry, University of California at Berkeley, Berkeley, CA 94720, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.forename: Albert E
authors.initials: AE
authors.lastname: Beuscher
authors.forename: Scott E
authors.initials: SE
authors.lastname: Andryski
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: D000915:Antibody Affinity; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000378:metabolism; D005294:Ferrochelatase / Q000737:chemistry*; D006860:Hydrogen Bonding; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D008024:Ligands; D005294:Ferrochelatase