Abstract
We describe here computer-assisted homology models of the combiningsite structure of three polyreactive immunoglobulins. Template-based modelsof Fv (VL–VH) fragments were derived forthe surface IgM expressed by the malignant CD5 positive B cells from threepatients with chronic lymphocytic leukaemia (CLL). The conserved frameworkregions were constructed using crystal coordinates taken from highlyhomologous human variable domain structures (Pot and Hil). Complementaritydetermining regions (CDRs) were predicted by grafting loops, taken fromknown immunoglobulin structures, onto the Fv framework models. The CDRtemplates were chosen, where possible, to be of the same length and of highresidue identity or similarity. LCDR1, 2 and 3 as well as HCDR1 and 2 forthe Fv were constructed using this strategy. For HCDR3 prediction, adatabase containing the Cartesian coordinates of 30 of these loops wascompiled from unliganded antibody X-ray crystallographic structures and anHCDR3 of the same length as that of the B CLL Fv was selected as a template.In one case (Yar), the resulting HCDR3 model gave unfavourable interactionswhen incorporated into the Fv model. This HCDR3 was therefore modelled usingan alternative strategy of construction of the loop stems, using apreviously described HCDR3 conformation (Pot), followed by chain closurewith a β-turn. The template models were subjected to positionalrefinement using energy minimisation and molecular dynamics simulations(X-PLOR). An electrostatic surface description (GRASP) did not reveal acommon structural feature within the binding sites of the three polyreactiveFv. Thus, polyreactive immunoglobulins may recognise similar and multipleantigens through a diverse array of binding site structures.
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Amit, A.G., Mariuzza, R.A., Phillips, S.E.V. and Poljak, R.J., Science, 233 (1986) 747.
Colman, P.M., Laver, W.G., Varghese, J.N., Baker, A.T., Tulloch, P.A., Air, G.M. and Webster, R.G., Nature, 326 (1987) 358.
Herron, J.N., He, X.-M., Mason, M.L., Voss Jr., E.W. and Edmundson, A.B., Proteins Struct. Funct. Genet., 5 (1989) 271.
Herron, J.N., He, X.-M., Ballard, D.W., Blier, P.R., Pace, P.E., Bothwell, A.L.M., Voss Jr., E.W. and Edmundson, A.B., Proteins Struct. Funct. Genet., 11 (1991) 159.
Arevalo, J.H., Hassig, C.A., Stura, E.A., Sims, M.J., Taussig, M.J. and Wilson, I.A., J. Mol. Biol., 241 (1994) 663.
Barry, M.M., Mol, C.D., Anderson, W.F. and Lee, J.S., J. Biol. Chem., 269 (1994) 3623.
Bassolino-Klimas, D., Bruccoleri, R.E. and Subramaniam, S., Protein Sci., 1 (1992) 1465.
Bajorath, J., Bioconj. Chem., 5 (1994) 213.
Chothia, C., Lesk, A.M., Levitt, M., Amit, A.G., Mariuzza, R.A., Phillips, S.E.V. and Poljak, R.J., Science, 233 (1986) 755.
De la Paz, P., Sutton, B.J., Darsley, M.J. and Rees, A.R., EMBO J., 5 (1986) 415.
Martin, A.C.R., Cheetham, J.C. and Rees, A.R., Methods Enzymol., 203 (1991) 121.
Chothia, C., Lesk, A.M., Tramontano, A., Levitt, M., Smith-Gill, S.J., Sheriff, S., Padlan, E.A., Davies, D., Tulip, W.R., Colman, P.M., Spinelli, S., Alzari, P.M. and Poljak, R.J., Nature, 342 (1989) 877.
Chothia, C., Lesk, A.M., Gherardi, E., Tomlinson, I.M., Walter, G., Marks, J.D., Meirion, B.L. and Winter, G., J. Mol. Biol., 227 (1992) 799.
Bruccoleri, R.E. and Karplus, M., Biopolymers, 26 (1987) 137.
Bajorath, J. and Fine, R.M., Immunomethods, 1 (1992) 137.
Sali, A., Curr. Opin. Biotechnol., 6 (1995) 437.
Nicholls, A. and Honig, B., J. Comput. Chem., 12 (1991) 435.
Brunger, A.T., X-PLOR v. 3.1. A System for X-ray Crystallography and NMR, Yale University Press, New Haven, CT, U.S.A., 1992.
Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.
Guddat, L.W., Shan, L., Anchin, J.M., Linthicum, D.S. and Edmundson, A.B., J. Mol. Biol., 236 (1994) 247.
Fan, Z.C., Shan, L., Guddat, L.W., He, X.-M., Gray, W.R., Raison, R.L. and Edmundson, A.B., J. Mol. Biol., 228 (1992) 188.
Kabat, E.A., Wu, T.T., Perry, H.M., Gottesman, K.S. and Foeller, C., Sequences of Proteins of Immunological Interest, 5th ed., National Institutes of Health, Bethesda, MD, U.S.A., 1991.
Wilmot, C.M. and Thornton, J.M., J. Mol. Biol., 203 (1988) 221.
Powell, M.J.D., Math. Programming, 12 (1977) 241.
Engh, R.A. and Huber, R., Acta Crystallogr., A47 (1991) 392.
Ramachandran, G.N. and Sasisekharan, V., Adv. Protein Chem., 23 (1968) 283.
He, X.-M., Ruker, F., Casale, E. and Carter, D.C., Proc. Natl. Acad. Sci. USA, 89 (1992) 7154.
Wu, T.T., Johnson, G. and Kabat, E.A., Proteins Struct. Funct. Genet., 16 (1993) 1.
Avrameas, S. and Ternynck, T., Mol. Immunol., 30 (1993) 1133.
Cheung, S.C., Takeda, S. and Notkins, A.L., Clin. Exp. Immunol., 101 (1995) 383.
Padlan, E.A., Mol. Immunol., 31 (1994) 231.
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Ramsland, P.A., Guddat, L.W., Edmundson, A.B. et al. Diverse binding site structures revealed in homology models of polyreactive immunoglobulins. J Comput Aided Mol Des 11, 453–461 (1997). https://doi.org/10.1023/A:1007932211514
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DOI: https://doi.org/10.1023/A:1007932211514