Structural Study on the Impact of S239D/I332E Mutations in the Binding of Fc and FcγRIIIa

Petrina Jebamani, Dinesh Kumar Sriramulu, Sang Taek Jung, Sun Gu Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Engineering of Fc for improved affinity to its receptor, FcγRIIIa, can enhance the therapeutic activity of monoclonal antibodies. S239D/I332E mutation of Fc has been extensively employed in various Fc engineering studies. Still, it is not clear how the mutations have structurally influenced the molecular interactions between Fc and FcγRIIIa. In this study, the point or combined mutations of S239D/I332E were introduced into one chain (A) or the other chain (chain B) of the homodimeric Fc domain computationally. Their structural effects on the binding to FcγRIIIa were investigated through a computational docking method. These results showed that the chain-specific point mutation, S239D induced a new salt-bridge with the receptor in A and B chains of Fc, whereas I332E mutation generated a new salt-bridge with the receptor only in A chain. The combined mutation study identified that the Fc variant with four mutations reproduced the three salt-bridges. This showed that the mutation of S239D and I332E in chain A of Fc induced complex salt-bridge formation with the Lys158 of FcγRIIIa. This study is expected to provide more structural insight into Fc variants’ design based on S239D/I332E mutation.

Original languageEnglish
Pages (from-to)985-992
Number of pages8
JournalBiotechnology and Bioprocess Engineering
Volume26
Issue number6
DOIs
Publication statusPublished - 2021 Dec

Keywords

  • Fc
  • FcγRIIIa
  • in silico mutation
  • protein-protein docking
  • salt-bridges

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Biomedical Engineering

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