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Modulation of antibody affinity by a non‐contact residue
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| Zeitschriftentitel: | Protein Science |
|---|---|
| Personen und Körperschaften: | , , , , , , , |
| In: | Protein Science, 2, 1993, 2, S. 206-214 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| author_facet |
Schildbach, Joel F. Near, Richard I. Bruccoleri, Robert E. Haber, Edgar Jeffrey, Philip D. Novotny, Jiri Sheriff, Steven Margolies, Michael N. Schildbach, Joel F. Near, Richard I. Bruccoleri, Robert E. Haber, Edgar Jeffrey, Philip D. Novotny, Jiri Sheriff, Steven Margolies, Michael N. |
|---|---|
| author |
Schildbach, Joel F. Near, Richard I. Bruccoleri, Robert E. Haber, Edgar Jeffrey, Philip D. Novotny, Jiri Sheriff, Steven Margolies, Michael N. |
| spellingShingle |
Schildbach, Joel F. Near, Richard I. Bruccoleri, Robert E. Haber, Edgar Jeffrey, Philip D. Novotny, Jiri Sheriff, Steven Margolies, Michael N. Protein Science Modulation of antibody affinity by a non‐contact residue Molecular Biology Biochemistry |
| author_sort |
schildbach, joel f. |
| spelling |
Schildbach, Joel F. Near, Richard I. Bruccoleri, Robert E. Haber, Edgar Jeffrey, Philip D. Novotny, Jiri Sheriff, Steven Margolies, Michael N. 0961-8368 1469-896X Wiley Molecular Biology Biochemistry http://dx.doi.org/10.1002/pro.5560020209 <jats:title>Abstract</jats:title><jats:p>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, <jats:italic>J. Biol. Chem. 266</jats:italic>, 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 results suggest that each of the substituted side chains may be accommodated within the antibody without substantial structural rearrangement, and that none of these substituted side chains are able to contact hapten. These modeling results are consistent with the substituents at position 52 having only an indirect influence upon antibody affinity. The mutagenesis and modeling results suggest that even conservative replacements of non‐contact residues can alter affinity indirectly through their impact on contact residue placement.</jats:p> Modulation of antibody affinity by a non‐contact residue Protein Science |
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Wiley, 1993 |
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1993 |
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Protein Science |
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49 |
| title |
Modulation of antibody affinity by a non‐contact residue |
| title_unstemmed |
Modulation of antibody affinity by a non‐contact residue |
| title_full |
Modulation of antibody affinity by a non‐contact residue |
| title_fullStr |
Modulation of antibody affinity by a non‐contact residue |
| title_full_unstemmed |
Modulation of antibody affinity by a non‐contact residue |
| title_short |
Modulation of antibody affinity by a non‐contact residue |
| title_sort |
modulation of antibody affinity by a non‐contact residue |
| topic |
Molecular Biology Biochemistry |
| url |
http://dx.doi.org/10.1002/pro.5560020209 |
| publishDate |
1993 |
| physical |
206-214 |
| description |
<jats:title>Abstract</jats:title><jats:p>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, <jats:italic>J. Biol. Chem. 266</jats:italic>, 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 results suggest that each of the substituted side chains may be accommodated within the antibody without substantial structural rearrangement, and that none of these substituted side chains are able to contact hapten. These modeling results are consistent with the substituents at position 52 having only an indirect influence upon antibody affinity. The mutagenesis and modeling results suggest that even conservative replacements of non‐contact residues can alter affinity indirectly through their impact on contact residue placement.</jats:p> |
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| author | Schildbach, Joel F., Near, Richard I., Bruccoleri, Robert E., Haber, Edgar, Jeffrey, Philip D., Novotny, Jiri, Sheriff, Steven, Margolies, Michael N. |
| author_facet | Schildbach, Joel F., Near, Richard I., Bruccoleri, Robert E., Haber, Edgar, Jeffrey, Philip D., Novotny, Jiri, Sheriff, Steven, Margolies, Michael N., Schildbach, Joel F., Near, Richard I., Bruccoleri, Robert E., Haber, Edgar, Jeffrey, Philip D., Novotny, Jiri, Sheriff, Steven, Margolies, Michael N. |
| author_sort | schildbach, joel f. |
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| description | <jats:title>Abstract</jats:title><jats:p>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, <jats:italic>J. Biol. Chem. 266</jats:italic>, 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 results suggest that each of the substituted side chains may be accommodated within the antibody without substantial structural rearrangement, and that none of these substituted side chains are able to contact hapten. These modeling results are consistent with the substituents at position 52 having only an indirect influence upon antibody affinity. The mutagenesis and modeling results suggest that even conservative replacements of non‐contact residues can alter affinity indirectly through their impact on contact residue placement.</jats:p> |
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| imprint | Wiley, 1993 |
| imprint_str_mv | Wiley, 1993 |
| institution | DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1 |
| issn | 1469-896X, 0961-8368 |
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| language | English |
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| spelling | Schildbach, Joel F. Near, Richard I. Bruccoleri, Robert E. Haber, Edgar Jeffrey, Philip D. Novotny, Jiri Sheriff, Steven Margolies, Michael N. 0961-8368 1469-896X Wiley Molecular Biology Biochemistry http://dx.doi.org/10.1002/pro.5560020209 <jats:title>Abstract</jats:title><jats:p>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, <jats:italic>J. Biol. Chem. 266</jats:italic>, 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 results suggest that each of the substituted side chains may be accommodated within the antibody without substantial structural rearrangement, and that none of these substituted side chains are able to contact hapten. These modeling results are consistent with the substituents at position 52 having only an indirect influence upon antibody affinity. The mutagenesis and modeling results suggest that even conservative replacements of non‐contact residues can alter affinity indirectly through their impact on contact residue placement.</jats:p> Modulation of antibody affinity by a non‐contact residue Protein Science |
| spellingShingle | Schildbach, Joel F., Near, Richard I., Bruccoleri, Robert E., Haber, Edgar, Jeffrey, Philip D., Novotny, Jiri, Sheriff, Steven, Margolies, Michael N., Protein Science, Modulation of antibody affinity by a non‐contact residue, Molecular Biology, Biochemistry |
| title | Modulation of antibody affinity by a non‐contact residue |
| title_full | Modulation of antibody affinity by a non‐contact residue |
| title_fullStr | Modulation of antibody affinity by a non‐contact residue |
| title_full_unstemmed | Modulation of antibody affinity by a non‐contact residue |
| title_short | Modulation of antibody affinity by a non‐contact residue |
| title_sort | modulation of antibody affinity by a non‐contact residue |
| title_unstemmed | Modulation of antibody affinity by a non‐contact residue |
| topic | Molecular Biology, Biochemistry |
| url | http://dx.doi.org/10.1002/pro.5560020209 |