Structural classification of CDR‐H3 revisited: A lesson in antibody modeling

Abstract Among the six complementarity‐determining regions (CDRs) in the variable domains of an antibody, the third CDR of the heavy chain (CDR‐H3), which lies in the center of the antigen‐binding site, plays a particularly important role in antigen recognition. CDR‐H3 shows significant variability in its length, sequence, and structure. Although difficult, model building of this segment is the most critical step in antibody modeling. Since our first proposal of the “H3‐rules,” which classify CDR‐H3 structure based on amino acid sequence, the number of experimentally determined antibody structures has increased. Here, we revise these H3‐rules and propose an improved classification scheme for CDR‐H3 structure modeling. In addition, we determine the common features of CDR‐H3 in antibody drugs as well as discuss the concept of “antibody druggability,” which can be applied as an indicator of antibody evaluation during drug discovery. Proteins 2008. © 2008 Wiley‐Liss, Inc.