4nwt
Crystal structure of the anti-human NGF Fab APE1531Crystal structure of the anti-human NGF Fab APE1531
Structural highlights
FunctionPublication Abstract from PubMedDuring somatic hypermutation (SHM), deamination of cytidine by activation-induced cytidine deaminase (AID) and subsequent DNA repair generates mutations within immunoglobulin V-regions. Nucleotide insertions and deletions (indels) have recently been shown to be critical for the evolution of antibody binding. Affinity maturation of 53 antibodies using in vitro SHM in a non-B cell context was compared with mutation patterns observed for SHM in vivo. The origin and frequency of indels seen during in vitro maturation was similar to that in vivo. Indels are localized to CDRs, and secondary mutations within insertions further optimize antigen binding. Structure determination of an antibody matured in vitro and comparison with human-derived antibodies containing insertions reveals conserved patterns of antibody maturation. These findings indicate that AID acting on V region sequences is sufficient to initiate authentic formation of indels in vitro and in vivo, and that point mutations, indel formation and clonal selection form a robust, tripartite system for antibody evolution. Nucleotide insertions and deletions complement point mutations to massively expand the diversity created by somatic hypermutation of antibodies.,Bowers PM, Verdino P, Wang Z, da Silva Correia J, Chhoa M, Macondray G, Do M, Neben TY, Horlick RA, Stanfield RL, Wilson IA, King DJ J Biol Chem. 2014 Oct 15. pii: jbc.M114.607176. PMID:25320089[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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