Paratome: an online tool for systematic identification of antigen-binding regions in antibodies based on sequence or structure

Antibodies are capable of specifically recognizing and binding antigens. Identification of the antigen-binding site, commonly dubbed paratope, is of high importance both for medical and biological applications. To date, the identification of antigen-binding regions (ABRs) relies on tools for the identification of complementarity-determining regions (CDRs). However, we have shown that up to 22% of the residues that actually bind the antigen fall outside the traditionally defined CDRs. The Paratome web server predicts the ABRs of an antibody, given its amino acid sequence or 3D structure. It is based on a set of consensus regions derived from a structural alignment of a non-redundant set of all known antibody–antigen complexes. Given a query sequence or structure, the server identifies the regions in the query antibody that correspond to the consensus ABRs. An independent set of antibody–antigen complexes was used to test the server and it was shown to correctly identify at least 94% of the antigen-binding residues. The Paratome web server is freely available at http://www.ofranlab.org/paratome/.

[1]  P E Bourne,et al.  Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. , 1998, Protein engineering.

[2]  David Schrama,et al.  Antibody targeted drugs as cancer therapeutics , 2006, Nature Reviews Drug Discovery.

[3]  A. Lesk,et al.  Standard conformations for the canonical structures of immunoglobulins. , 1997, Journal of molecular biology.

[4]  Chantal Abergel,et al.  Identification of specificity‐determining residues in antibodies , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  H. Bilofsky,et al.  Unusual distributions of amino acids in complementarity-determining (hypervariable) segments of heavy and light chains of immunoglobulins and their possible roles in specificity of antibody-combining sites. , 1977, The Journal of biological chemistry.

[6]  E A Padlan Structural implications of sequence variability in immunoglobulins. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[7]  V. Giudicelli,et al.  IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. , 2003, Developmental and comparative immunology.

[8]  C. Milstein,et al.  Reshaping human antibodies: grafting an antilysozyme activity. , 1988, Science.

[9]  M S Waterman,et al.  Identification of common molecular subsequences. , 1981, Journal of molecular biology.

[10]  B. Rost,et al.  Analysing six types of protein-protein interfaces. , 2003, Journal of molecular biology.

[11]  T. T. Wu,et al.  AN ANALYSIS OF THE SEQUENCES OF THE VARIABLE REGIONS OF BENCE JONES PROTEINS AND MYELOMA LIGHT CHAINS AND THEIR IMPLICATIONS FOR ANTIBODY COMPLEMENTARITY , 1970, The Journal of experimental medicine.

[12]  G. Winter,et al.  Selection of phage antibodies by binding affinity. Mimicking affinity maturation. , 1992, Journal of molecular biology.

[13]  Andrew C. Chan,et al.  Therapeutic antibodies for autoimmunity and inflammation , 2010, Nature Reviews Immunology.

[14]  Yanay Ofran,et al.  Structural Consensus among Antibodies Defines the Antigen Binding Site , 2012, PLoS Comput. Biol..

[15]  P. T. Jones,et al.  Replacing the complementarity-determining regions in a human antibody with those from a mouse , 1986, Nature.

[16]  Andrew J. Martin,et al.  Antibody-antigen interactions: contact analysis and binding site topography. , 1996, Journal of molecular biology.

[17]  B. Rost,et al.  Automated Identification of Complementarity Determining Regions (CDRs) Reveals Peculiar Characteristics of CDRs and B Cell Epitopes1 , 2008, The Journal of Immunology.

[18]  E. Kabat,et al.  Sequences of proteins of immunological interest , 1991 .

[19]  A. Lesk,et al.  Conformations of immunoglobulin hypervariable regions , 1989, Nature.

[20]  J. C. Almagro,et al.  Identification of differences in the specificity‐determining residues of antibodies that recognize antigens of different size: implications for the rational design of antibody repertoires , 2004, Journal of molecular recognition : JMR.

[21]  Ulrik B. Nielsen,et al.  Affinity Maturation by Chain Shuffling and Site Directed Mutagenesis , 2001 .

[22]  A. Lesk,et al.  Canonical structures for the hypervariable regions of immunoglobulins. , 1987, Journal of molecular biology.