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To enhance our understanding of how recognition and specificity for different ligands can be accomplished by related antibodies, we are studying the evolution of ligand binding properties by site-directedmutagenesis. Themost active catalytic Diels-Alder antibody known to date, 1E9, and the steroid binding antibody, DB3, derive from the same polyspecific germ line sequences and share 85% sequence identity. In spite of their close relationship, they fulfill very different specific tasks with high efficiency. Through sequential amino acid exchanges, we changed the specificity of 1E9 to that of DB3. Binding studies reveal that just a few residues are predominantly responsible for achieving either an efficient catalysis of the Diels-Alder reaction or, when mutated, convert the 1E9 Fab into a strong steroid binder. We determined the structures of the 1E9 mutants as apo-proteins, as well as in complex with different steroids. The structures highlight that only two residues in the substrate binding site are necessary and sufficient for discriminating structurally diverse ligands. Additionally, the structures reveal that despite strong binding (nM Kds) several distinct binding modes are employed promiscuously in order to accommodate structurally different steroids in the engineered ligand binding sites. The potential of antibodies as biocatalysts and the clinical utility of diagnostic and therapeutic antibodies have been the impetus behind the rapid development of antibody engineering. Our studies contribute to the advancement of this field by demonstrating how relativelyminor changes can be rationally employed to modify antibody specificity and function.

acta crystallographica. section a, foundations of crystallography/acta crystallographica. section a

Formation of amyloid fibres followed by X-ray diffraction in real time. Implications for the identity of bio-active species in conformational diseases like Alzheimer's disease