4J1U

Crystal structure of antibody 93F3 unstable variant

Summary for 4J1U

• Entry DOI: 10.2210/pdb4j1u/pdb
• Descriptor: antibody 93F3 Light chain, antibody 93F3 Heavy chain (3 entities in total)
• Functional Keywords: antibody maturation, antibody stability, clonal selection, immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 6
• Total formula weight: 148028.69

Authors

Wang, F. (deposition date: 2013-02-02, release date: 2013-03-13, Last modification date: 2024-10-16)

Primary citation

Wang, F.,Sen, S.,Zhang, Y.,Ahmad, I.,Zhu, X.,Wilson, I.A.,Smider, V.V.,Magliery, T.J.,Schultz, P.G.
Somatic hypermutation maintains antibody thermodynamic stability during affinity maturation.
Proc.Natl.Acad.Sci.USA, 110:4261-4266, 2013

PubMed Abstract: Somatic hypermutation and clonal selection lead to B cells expressing high-affinity antibodies. Here we show that somatic mutations not only play a critical role in antigen binding, they also affect the thermodynamic stability of the antibody molecule. Somatic mutations directly involved in antigen recognition by antibody 93F3, which binds a relatively small hapten, reduce the melting temperature compared with its germ-line precursor by up to 9 °C. The destabilizing effects of these mutations are compensated by additional somatic mutations located on surface loops distal to the antigen binding site. Similarly, somatic mutations enhance both the affinity and thermodynamic stability of antibody OKT3, which binds the large protein antigen CD3. Analysis of the crystal structures of 93F3 and OKT3 indicates that these somatic mutations modulate antibody stability primarily through the interface of the heavy and light chain variable domains. The historical view of antibody maturation has been that somatic hypermutation and subsequent clonal selection increase antigen-antibody specificity and binding energy. Our results suggest that this process also optimizes protein stability, and that many peripheral mutations that were considered to be neutral are required to offset deleterious effects of mutations that increase affinity. Thus, the immunological evolution of antibodies recapitulates on a much shorter timescale the natural evolution of enzymes in which function and thermodynamic stability are simultaneously enhanced through mutation and selection.

PubMed: 23440204
DOI: 10.1073/pnas.1301810110

Experimental method

X-RAY DIFFRACTION (2.58 Å)