Hostname: page-component-cd9895bd7-p9bg8 Total loading time: 0 Render date: 2024-12-27T12:29:44.842Z Has data issue: false hasContentIssue false

Structural basis for the specificity of antibody–antigen reactions and structural mechanisms for the diversification of antigen-binding specificities

Published online by Cambridge University Press:  17 March 2009

Eduardo A. Padlan
Affiliation:
Laboratory of Molecular Biology, National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014, U.S.A.

Extract

The ability of an organism to cope with foreign substances (antigens) depends in part on its capacity to synthesize antibodies (immunoglobulins) of the proper binding specificity to recognize and combine with these antigens. In view of the great variety of possible antigens, antibodies, or more specifically their combining sites, display considerable variation and possess structural properties such as to enable them to bind the antigenic determinants. A vast amount of immunoglobulin sequence data has become available and the three-dimensional structures of a number of immunoglobulin fragments have been elucidated. With these results we can now begin to understand the structural aspects of antibody–antigen reactions. The crystallographic results and the sequence data have been reviewed elsewhere (Capra & Kehoe, 1975; Davies, Padlan & Segal 1975a, b; Gally, 1973; Kabat, 1976; Nisonoff, Hopper & Spring, 1975; Poljak, 1975a, b). Here, an attempt is made to interpret these structural data in terms of the structural evolution of the antibody combining site and the structural basis for the specificity of the binding of antibody to antigen. First, the pertinent crystallographic and sequence data will be presented. Next, the structural studies which reveal the complementarity between antibody and ligand will be described. Then, structural mechanisms by which different combining site structures could be generated will be reviewed.

Type
Research Article
Copyright
Copyright © Cambridge University Press 1977

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Amzel, L. M., Poljak, R. J., Saul, F., Varga, J. M. & Richards, F. F. (1974) The three-dimensional structure of a combining region ligand complex of immunoglobulin NEW at 3·5 A resolution. Proc. natn. Acad. Sci. U.S.A. 71, 1427–30.CrossRefGoogle ScholarPubMed
Barstad, P., Rudikoff, S., Potter, M., Cohn, M., Konigsberg, W. & Hood, L. (1974). Immunoglobulin structure: aminoterminal sequences of mouse myeloma proteins that bind phophorylcholine. Science, N.Y. 183, 962–4.CrossRefGoogle Scholar
Capra, J. D. & Kehoe, J. M. (1974). Variable region sequences of five human immuoglobulin heavy chains of the VHIIl subgroup: definitive identification of four heavy chain hypervariable regions. Proc. natn. Acad. Sci. U.S.A. 71, 845–8CrossRefGoogle Scholar
Capra, J. D. & Kehoe, J. M. (1975). Hypervariable regions, idiotypy and the antibody combining site. Adv. Immun. 20, 140.CrossRefGoogle ScholarPubMed
Cebra, J. J., Koo, P. H. & Ray, A. (1974). Specificity of antibodies: primary structural basis of hapten binding. Science, N.Y. 186, 263–5.CrossRefGoogle ScholarPubMed
Cesari, I. M. & Weigert, M. (1973). Mouse lambda-chain sequences. Proc. natn. Acad. Sci. U.S.A. 70, 2112–16.CrossRefGoogle ScholarPubMed
Claflin, J. L., Lieberman, R. & Davie, J. M. (1974). Clonal nature of the immune response to phosphorylcholine. II. Idiotypic specificity and binding characteristics of anti-phosphorylcholine antibodies. J. Immun. 112, 1747–56.CrossRefGoogle ScholarPubMed
Colman, P. M., Deisenhofer, J., Huber, R. & Palm, W. (1976). Structure of the human antibody molecule Kol (Immunoglobulin Gl): An electron density map at 5A resolution. J. molec. Biol. 100, 157–8.CrossRefGoogle Scholar
Davies, D. R., Padlan, E. A. & Segal, D. M. (1975 a). Three-dimensional structure of immunoglobulins. A. Rev. Biochem. 44, 639–67.CrossRefGoogle ScholarPubMed
Davies, D. R., Padlan, E. A. & Segal, D. M. (1975 b). Immunoglobulin structures at high resolution. In Contemporary Topics in Molecular Immunology, vol. 4 (ed. Inman, F. P. and Mandy, W. J.), pp. 127–55. New York: Plenum Press.CrossRefGoogle Scholar
Davies, D. R. & Padlan, E. A. (1975). Correlations between antigen-binding specificity and the three-dimensional structure of the antibody combining sites. In Proceedings of the Royal Society of Medicine Symposium (20–22 Oct. 1975; Rockefeller University). New York: Raven Press (in the Press).Google Scholar
Dayhoff, M. (1972). Atlas of Protein Sequence and Structure. Washington, DC: National Biomedical Research Foundation.Google Scholar
Deisenhofer, J., Colman, P. M. & Huber, R. (1976). Crystallographic structural studies of a human Fc-fragment. I. An electron-density map at 4 A resolution and a partial model. Hoppe-Seyler's Z. Physiol. Chem. 357, 435–45.CrossRefGoogle Scholar
Edelman, G. M., Cunningham, B. A., Gall, W. E., Gottlieb, P. D., Rutishauser, U. & Waxdal, M. J. (1969). The covalent structure of an entire gamma G immunoglobulin molecule. Proc. natn. Acad. Sci. U.S.A. 63, 7885.CrossRefGoogle Scholar
Edmundson, A. B., Ely, K. R., Girling, R. L., Abola, E. E., Schiffer, M., Westholm, F. A., Fausch, M. D. & Deutsch, H. F. (1974). Binding of 2,4-dinitrophenyl compounds and other small molecules to a crystalline lambda-type Bence-Jones dimer. Biochemistry, N. Y. 13, 3816–27.CrossRefGoogle Scholar
Edmundson, A. B., Ely, K. R., Abola, E. E., Schiffer, M. & Panagioto-Poulos, N. (1975). Rotational allomerism and divergent evolution of domains in immunoglobulin light chains. Biochemisty, N.Y. 14, 3953–61.CrossRefGoogle Scholar
Epp, O., Colman, P., Fehlhammer, H., Bode, W., Schiffer, M., Huber, R. & Palm, W. (1974). Crystal and molecular structure of a dimer composed of the variable portions of the Bence-Jones protein REI. Eur. J. Biochem. 45, 513–24.CrossRefGoogle ScholarPubMed
Fehlhammer, H., Schiffer, M., Epp, O., Colman, P. M., Lattman, E. E., Schwager, P., Steigemann, W. & Schramm, H. J. (1975). The structure determination of the variable portion of the Bence-Jones Protein Au. Biophys. Struct. Mechanism 1, 139–46.CrossRefGoogle ScholarPubMed
Fett, J. W. & Deutsch, H. F. (1974). Primary structure of the Mcg lambda chain. Biochemistry, N.Y. 13, 4102–14.CrossRefGoogle ScholarPubMed
Gally, J. E. (1973). Structure of immunoglobulins. In The Antigens, vol. I (ed. Sela, M.), pp. 161298. New York, London: Academic Press.CrossRefGoogle Scholar
Grossberg, A. L., Krausz, L. M., Rendina, L. & Pressman, D. (1974). The presence of arginyl residues and carboxylate groups in the phosphorylcholine binding site of mouse myeloma protein, HOPC 8. J. Immun. 113, 1807–14.CrossRefGoogle ScholarPubMed
Hood, L., Campbell, J. H. & Elgin, S. C. R. (1975). The organization, expression and evolution of antibody gene families. A. Rev. Genet. 9, 305–53.CrossRefGoogle Scholar
Jaton, J.-C. (1974). Comparison of the amino acid sequences of the variable domains of two homogenous rabbit antibodies to type III pneumococcal polysaccharide. Biochem. J. 147, 235–47.CrossRefGoogle Scholar
Kabat, E. A. (1976). Structural Concepts in Immunology and Immunochemistry. New York: Holt, Rinehart & Winston.Google Scholar
Kabat, E. A., Padlan, E. A. & Davies, D. R. (1975). Evolutionary and structural influences in light chain constant (CL) region of human and mouse immunoglobulins. Proc. natn. Acad. Sci. U.S.A. 72, 2785–8.CrossRefGoogle ScholarPubMed
Kabat, E. A. & Wu, T. T. (1971). Attempts to locate complementarity-determining residues in the variable positions of light and heavy chains. Ann. N.Y. Acad. Sci. 190, 382–93.CrossRefGoogle ScholarPubMed
Kabat, E. A., Wu, T. T. & Bilofsky, H. (1976). Attempts to locate residues in complementarity-determining regions of antibody combining sites that make contact with antigen. Proc. natn. Acad. Sci. U.S.A. 73, 617–19.CrossRefGoogle ScholarPubMed
Leon, M. A. & Young, M. N. (1971). Specificity for phosphorylcholine of six murine myeloma proteins reactive with pneumococcus C polysaccharide and beta-lipoprotein. Biochemistry, N.Y. 10, 1424–9.CrossRefGoogle ScholarPubMed
Low, T. L. K., Liu, Y.-S. V. & Putnam, F. W. (1976). Structure, function and evolutionary relationships of Fc domains of human immunoglobulins A, G, M and E. Science, N.Y. 191, 390–2.CrossRefGoogle Scholar
Margolies, M. N., Cannon, L. E. III, Strosberg, A. D. & Haber, E. (1975) Diversity of light chain variable region sequences among rabbit antibodies elicited by the same antigens. Proc. natn. Acad. Sci. U.S.A. 72, 2180–4.CrossRefGoogle ScholarPubMed
McKean, D., Potter, M. & Hood, L. (1973). Mouse immunoglobulin chains. Pattern of sequence variation among kappa-chains with limited sequence differences. Biochemistry, N.Y. 12, 760–71.CrossRefGoogle ScholarPubMed
Metzger, H. (1974). Effect of antigen binding on the properties of antibody Adv. Immun. 18, 169207.CrossRefGoogle ScholarPubMed
Metzger, H., Chesebro, B., Hadler, N. M., Lee, J. & Otchin, N. (1971). Modification of immunoglobulin combining sites. In Progress in Immunology (ed. Amos, B.), pp. 253–67. New York, London: Academic Press.CrossRefGoogle Scholar
Nisonoff, A., Hopper, J. E. & Spring, S. B. (1975). The Antibody Molecule. New York, London: Academic Press.Google Scholar
Novotny, J. & Franek, F. (1975) Different degrees of interspecies homology in immunoglobulin lambda chain constant domain correlated with three-dimensional structure. Nature 258, 641–3.CrossRefGoogle ScholarPubMed
Padlan, E. A., Segal, D. M., Spande, T. F., Davies, D. R., Rudikoff, S. & Potter, M. (1973). Structure at 4·5 A resolution of a phosphorylcholinebinding Fab. Nature (New Biol.) 145, 165–7.CrossRefGoogle Scholar
Padlan, E. A., Segal, D. M., Cohen, G. H., Davies, D. R., Rudikoff, S. & Potter, M. (1974). The three-dimensional structure of the antigen binding site of McPC603 protein. In The Immune System (ed. Sercarz, E. E., Williamson, A. R. and Cox, C. F.) pp. 714. New York, London: Academic Press.CrossRefGoogle Scholar
Padlan, E. A. & Davies, D. R. (1975). Variability of three-dimensional structure in immunoglobulins. Proc. natn. Acad. Sci. U.S.A. 72, 819–23.CrossRefGoogle ScholarPubMed
Padlan, E. A., Davies, D. R., Pecht, I., Givol, D. & Wright, C. (1976 a) Model building studies of antigen binding sites: The hapten binding site of MOPC 315. Cold Spring Harb. Symp. Quant. Biol. (in the Press).Google Scholar
Padlan, E. A., Davies, D. R., Rudikoff, S. & Potter, M. (1976 b). Structural basis for the specificity of phosphorylcholine-binding immunoglobulins. Immunochem. 13, 945–9.CrossRefGoogle ScholarPubMed
Poljak, R. J., Amzel, L. M., Avey, H. P., Chen, B. L., Phizackerley, R. P. & Saul, F. (1973). Three-dimensional structure of the Fab′ fragment of a human immunoglobulin at 2·8 A resolution. Proc. natn. Acad. Sci. U.S.A. 70, 3305–10.CrossRefGoogle ScholarPubMed
Poljak, R. J., Amzel, L. M., Chen, B. L., Phizackerley, R. P. & Saul, F. (1974). The three-dimensional structure of the Fab′ fragment of a human myeloma immunoglobulin at 2·o A resolution. Proc. natn. Acad. Sci. U.S.A. 71, 3440–4.CrossRefGoogle Scholar
Poljak, R. J. (1975 a). X-ray diffraction studies of immunoglobulins Adv. Immun. 21, 133.CrossRefGoogle ScholarPubMed
Poljak, R. J. (1975 b). Three-dimensional structure, function and genetic control of immunoglobulins. Nature, Lond. 256, 373–6.CrossRefGoogle ScholarPubMed
Ponstingl, H., Schwarz, J., Reichel, W. & Hilschmann, N. (1970). Die primaerstruktur eines monoklonen gamma 1-immunoglobulins (myelomaprotein Nie), I aminosaeuresequenz des variablen teiles der H-kette, subgruppen variabler teile. Hoppe-Seyler's Z. Physiol. Chem. 351, 1591–4.Google Scholar
Potter, M. (1971). Antigen-binding myeloma proteins in mice. Ann. N.Y. Acad. Sci. 190, 382–93.CrossRefGoogle ScholarPubMed
Potter, M. (1972). Immunoglobulin-producing tumors and myeloma proteins of mice. Physiol. Rev. 52, 631719.CrossRefGoogle ScholarPubMed
Potter, M. & Lieberman, R. (1970). Common individual antigenic determinants in five of eight BALB/c IgA myeloma proteins that bind phosphoryicholine. J. exp. Med. 132, 737–51.CrossRefGoogle Scholar
Potter, M., Rudikoff, S., Padlan, E. A. & Vrana, M. (1975). The covalent structure of the antigen-binding site: antigen-binding myeloma proteins of the BALB-c mouse. In Proceedings of the Royal Society of Medicine Symposium (20–22 Oct, 1975; Rockefeller University). New York: Raven Press (in the Press).Google Scholar
Potter, M., Padlan, E. A. & Rudikoff, S. (1976). Localized deletion–insertion mutations: a major factor in the evolution of immunoglobulin structural variability. J. immun. (in the Press).CrossRefGoogle Scholar
Putnam, F. W., Florent, G., Paul, C., Shinoda, T. & Shimizu, A. (1973). Complete amino acid sequence of the Mu heavy chain of a human IgM immunoglobulin. Science, N.Y. 181, 287–91.CrossRefGoogle Scholar
Riesen, W. F., Braun, D. G. & Jaton, J.-C. (1976). Human and murine phosphorylcholine binding immunoglobulins: conserved subgroup and first hypervariable region of the heavy chains. Proc. natn. Acad. Sci. U.S.A. 73, 20962100.CrossRefGoogle ScholarPubMed
Rudikoff, S. & Potter, M. (1974). Variable region sequence of the heavy chain from a phosphorylcholine binding myeloma protein. Biochemistry, N.Y. 13, 4033–8.CrossRefGoogle ScholarPubMed
Rudikoff, S. & Potter, M. (1976). Size differences among immunoglobulin heavy chains from phosphorylcholine binding proteins. Proc. natn. Acad. Sci. U.S.A. (in the Press).CrossRefGoogle ScholarPubMed
Schiffer, M., Girling, R. L., Ely, K. R. & Edmundson, A. B. (1973). Structure of a lambda-type Bence-Jones protein at 3·5 A resolution. Biochemisty, N.Y. 12, 4620–31.CrossRefGoogle ScholarPubMed
Segal, D. M., Padlan, E. A., Cohen, G. H., Silverton, E. W., Davies, D. R., Rudikoff, S. & Potter, M. The structure of McPC603 Fab and its hapten complex. In Progress in Immunology, II, vol 1: Immunochemical Aspects (ed. Brent, L. and Holborow, J.), pp. 93102. Amsterdam: North-Holland Publishing Co.Google Scholar
Segal, D. M., Padlan, E. A., Cohen, G. H., Rudikoff, S., Potter, M. & Davies, D. R. (1974 b). The three-dimensional structure of a phosphorylcholine-binding mouse immunoglobulin Fab and the nature of the antigen binding site. Proc. natn. Acad. Sci. U.S.A. 71, 42984302.CrossRefGoogle ScholarPubMed
Svasti, J. & Milstein, C. (1972). The complete amino acid sequence of a mouse κ light chain. Biochem. J. 128, 427–44.CrossRefGoogle ScholarPubMed
Wu, T. T. & Kabat, E. A. (1970). An analysis of the sequences of the variable regions of Bence-Jones proteins and myeloma light chains and their implication for antibody complementarity. J. exp. Med. 132, 211–49.CrossRefGoogle ScholarPubMed