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Review
. 2013 Oct 8:4:302.
doi: 10.3389/fimmu.2013.00302.

The structural basis of antibody-antigen recognition

Inbal Sela-Culang  1 , Vered Kunik, Yanay Ofran
Affiliations
Review

The structural basis of antibody-antigen recognition

Inbal Sela-Culang et al. Front Immunol. .

Abstract

The function of antibodies (Abs) involves specific binding to antigens (Ags) and activation of other components of the immune system to fight pathogens. The six hypervariable loops within the variable domains of Abs, commonly termed complementarity determining regions (CDRs), are widely assumed to be responsible for Ag recognition, while the constant domains are believed to mediate effector activation. Recent studies and analyses of the growing number of available Ab structures, indicate that this clear functional separation between the two regions may be an oversimplification. Some positions within the CDRs have been shown to never participate in Ag binding and some off-CDRs residues often contribute critically to the interaction with the Ag. Moreover, there is now growing evidence for non-local and even allosteric effects in Ab-Ag interaction in which Ag binding affects the constant region and vice versa. This review summarizes and discusses the structural basis of Ag recognition, elaborating on the contribution of different structural determinants of the Ab to Ag binding and recognition. We discuss the CDRs, the different approaches for their identification and their relationship to the Ag interface. We also review what is currently known about the contribution of non-CDRs regions to Ag recognition, namely the framework regions (FRs) and the constant domains. The suggested mechanisms by which these regions contribute to Ag binding are discussed. On the Ag side of the interaction, we discuss attempts to predict B-cell epitopes and the suggested idea to incorporate Ab information into B-cell epitope prediction schemes. Beyond improving the understanding of immunity, characterization of the functional role of different parts of the Ab molecule may help in Ab engineering, design of CDR-derived peptides, and epitope prediction.

Keywords: CDRs; antibody; antigen; constant domain; epitope; framework; paratope.

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Figures

Figure 1
Figure 1
Predicted epitopes vs. the actual epitopes of HEL. (A) The 3-D structure of HEL (CPK representation) together with three Abs (ribbon representation). PDB IDs 1JHL, 3D9A, and 1MLC were superimposed according to HEL structure. Epitope residues are colored blue, green, and red according to the corresponding Ab. Residues that are common to two epitopes are colored orange. (B) The structure of HEL colored according to the same three epitopes as in (A), presented in a different orientation. (C) The structure of HEL colored according to the epitopes predicted by Discotope (light blue), ellipro (purple), and seppa (pink). Note, not all predicted residues of Discotope and ellipro are observable in the presented orientation.
Figure 2
Figure 2
The structure of an Ab molecule. (A) The 3-D structure of an Ab molecule (PDB ID: 1IGT). (B) A schematic representation of the Ab scaffold.
Figure 3
Figure 3
Comparison of different CDR identification methods. The light (A) and heavy (B) chains of PDB ID 2XQB were numbered according to Kabat (colored green) and Chothia (colored red) using the Abnum tool (www.bioinf.org.uk/abs/abnum) and CDRs were extracted according to the CDR definitions table (www.bioinf.org.uk/abs/#cdrs). CDRs according to IMGT (colored orange) were identified using the IMGT-gap tool (www.imgt.org/3Dstructure-DB/cgi/DomainGapAlign.cgi). ABRs according to Paratome (colored blue) were identified using the Paratome server (www.ofranlab.org/paratome). Contacts (colored purple) between the Ab and IL-15 were defined using a 6-Å cutoff value.
Figure 4
Figure 4
Ab positions that contact the Ag. (A,B) The lower graphs show the percentage of Abs with known 3-D structure that have a residue in a given position (i.e., in other Abs there is a gap in the MSTA in that position). The upper graphs show the percentage of Abs that contact the Ag out of those Abs that have a residue in that position. (A) Depicts the heavy chain and (B) depicts the light chain. In the upper graphs, the ABRs are colored red and the FRs are colored blue. An example of a position within an ABR that is not in contact with the Ag in any of the Abs, is marked by a green arrow. An example of a position in the FRs that is in contact with the Ag in many (8%) of the Abs is marked by an orange arrow. (C) The Ab Fv domain (PDB ID: 1QFU) is colored according to the percentage of all Abs with known 3-D structure in which the residue in that position is in contact with the Ag: from red (100% of the Abs) to blue (0%). ABR residues are presented as lines. The definition of the ABRs is according to the Paratome server. A 6-Å cutoff value was used to define residues in contact. Percentages of contacts were calculated based on an MSTA of all protein Ab-Ag complexes in the PDB (30).
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