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Structural plasticity and the evolution of antibody affinity and specificity
Jun Yin1, Albert E Beuscher, Scott E Andryski
1Department of Chemistry, University of California at Berkeley, Berkeley, CA 94720, USA.
Journal of Molecular Biology
|July 10, 2003
Summary
The germline antibody precursor 7G12 binds both its target and other molecules. Somatic mutations enhance specificity for the target, demonstrating a key immune system mechanism for receptor evolution.
Area of Science:
- Immunology
- Structural Biology
- Protein Engineering
Background:
- Antibodies evolve through somatic hypermutation to improve binding affinity and specificity.
- Understanding the structural basis of antibody maturation is crucial for designing targeted therapeutics.
Purpose of the Study:
- To investigate the structural changes in the germline antibody precursor 7G12 during affinity maturation.
- To elucidate the role of somatic mutations in enhancing hapten binding and reducing non-hapten binding.
Main Methods:
- X-ray crystallography was used to determine the structures of the germline antibody precursor 7G12 in complex with its hapten (N-methylmesoporphyrin) and a non-hapten ligand (jeffamine).
- Structural comparisons were made between the germline antibody, the antibody-ligand complexes, and the affinity-matured antibody.
Main Results:
- The germline antibody precursor 7G12 exhibits conformational plasticity, binding both its cognate hapten and the structurally distinct jeffamine.
- Somatic mutations significantly enhance binding affinity for the hapten while decreasing affinity for jeffamine.
- Somatic mutations stabilize the binding site for the hapten and introduce steric hindrances for non-hapten molecules.
Conclusions:
- Antibody affinity maturation involves significant conformational changes that optimize binding to the target antigen.
- Somatic mutations are critical for refining antibody specificity by enhancing target binding and excluding off-target interactions.
- The observed mechanisms of structural plasticity and mutation-driven specificity likely represent general principles in the evolution of high-affinity receptors.