Modulation of antibody affinity by a non-contact residue

Protein Science : a Publication of the Protein Society
J F SchillbachM N Margolies

Abstract

Antibody LB4, produced by a spontaneous variant of the murine anti-digoxin monoclonal antibody 26-10, has an affinity for digoxin two orders of magnitude lower than that of the parent antibody due to replacement of serine with phenylalanine at position 52 of the heavy chain variable region (Schildbach, J.F., Panka, D.J., Parks, D.R., et al., 1991, J. Biol. Chem. 266, 4640-4647). To examine the basis for the decreased affinity, a panel of engineered antibodies with substitutions at position 52 was created, and their affinities for digoxin were measured. The antibody affinities decreased concomitantly with increasing size of the substituted side chains, although the shape of the side chains also influenced affinity. The crystal structure of the 26-10 Fab complexed with digoxin (P.D.J., R.K. Strong, L.C. Sieker, C. Chang, R.L. Campbell, G.A. Petsko, E.H., M.N.M., & S.S., submitted for publication) shows that the serine at heavy chain position 52 is not in contact with hapten, but is adjacent to a tyrosine at heavy chain position 33 that is a contact residue. The mutant antibodies were modeled by applying a conformational search procedure to position side chains, using the 26-10 Fab crystal structure as a starting point. The result...Continue Reading

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Citations

May 1, 1994·Protein Science : a Publication of the Protein Society·J F SchildbachR I Near
Apr 28, 1995·Journal of Molecular Biology·P D JeffreyS Sheriff
Feb 1, 1997·Molecular Immunology·N Rauffer-BruyreD Altschuh
Sep 3, 2002·Biochimica Et Biophysica Acta·Banerjee AshishGundlupet Satyanarayana Murthy
Aug 12, 2008·Proceedings of the National Academy of Sciences of the United States of America·Petra VerdinoIan A Wilson
Nov 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·P D JeffreyS Sheriff
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