Sequencing and modeling of anti-DNA immunoglobulin Fv domains. Comparison with crystal structures.

M.M Barry,C.D Mol,W.F Anderson,J.S Lee

doi:10.1016/s0021-9258(17)41908-9

M.M Barry, C.D Mol + Show 2 more

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https://doi.org/10.1016/s0021-9258(17)41908-9

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Abstract

Models for the three-dimensional structures of the combining regions of six DNA-binding antibodies have been derived from the sequence data for their Fv domains presented here. Using the amino acid sequences and the canonical structure classes described by Chothia and Lesk (Chothia, C., and Lesk, A.M. (1987) J. Mol. Biol. 196, 901), model loops were selected from immunoglobulin domains of known structure for five of the six antibody hypervariable regions. Models for the third complementarity-determining region of the heavy chain were constructed from known immunoglobulin loops of similar length and sequence. Comparison of three of the models with the respective crystal structure indicates that this procedure can generate a working model of the antibody combining region that provides useful information on the nature of the interactions between antibodies and nucleic acids. As part of our continuing investigation into the structural basis of antibody-DNA recognition, the observed and predicted models for the combining regions of nucleic acid-binding antibodies have been examined. In general, single strand-specific antibodies have deep clefts where the antigen might bind, whereas duplex-specific antibodies present a relatively flat surface. In addition, on the basis of both sequence and structure, there is little to distinguish autoimmune antibodies from those produced by immunization. Testable hypotheses for how these antibodies might interact with single- and double-stranded nucleic acids are presented.

Highlights

From the Department of Biochemistry, the University of Saskatchewan, Saskatoon, Saskatchewan S7N OWO,Canada and the Wepartment of Biochemistry, Vanderbitt University, Nashville, Zknnessee 37232-0146
Two different methods for using amino acid sequence inforcombining regions of six DNA-binding antibodies have mation to predict the conformations of antibody hypervariable been derived &om the sequence data for their Fv do- loops have been previously employed
Biol. 196,Sol),model loops wereselected from immuno- Several groups have reported some success predicting protein globulin domains okf nown structure forfive of thesix loop conformations de nouo

Summary

Introduction

To extend our studies of DNA-binding antibodies, we have determined the sequences of the Fv domains of six murine anti-nucleic acid antibodies and used the canonical structure model (1, 5 ) to predict the loop conformations. DNA Binding ModeleAn examination of the relative disposition of the antibody CDRs and the electrostatic potential of the crystallographically determined structures has aided us in deriving testable hypotheses for how these antibodies may interact with their respective nucleic acidantigens.

Results

Conclusion