Conserved sequence and structure association motifs in antibody-protein and antibody-hapten complexes.
In this paper, we present the association requirements across a wide variety of antibody-antigen complexes. Phylogenetic analysis clearly indicates the representative nature of our structural dataset. Antigen molecules range from small-molecule haptens to complete protein structures. Common association motifs identified include five conserved tyrosine residues and a single conserved arginine residue from CDR-H3. Further, specificity is refined by a diverse array of antibody-antigen electrostatic interactions that maximize complex specificity. Through analysis of calculated pKa shifts on antigen binding, we find that these interactions are conserved at 23 alignment 'hot-spot' positions. Despite consistent roles in defining substrate specificity, 16 hot-spot positions are conserved less than 50% of the time. On the other hand, because of the conserved functional role of these positions, mutant screening at hot-spots is more likely to result in increased antigen specificity than elsewhere. Therefore, we believe these results should facilitate subsequent antibody design experimentation.
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana 61801, USA.
Dennis R
DR
Livesay
Shankar
S
Subramaniam
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology*; D019295:Computational Biology; D006241:Haptens / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein
D000906:Antibodies; D006241:Haptens