Leucine-rich repeat 2 of human Toll-like receptor 4 contains the binding site for inhibitory monoclonal antibodies

Hiroki Tsukamoto, Ippo Ukai, Yuki Yamagata, Shino Takeuchi, Kanae Kubota, Sao Kozakai, Naoto Suzuki, Masao Kimoto, Yoshihisa Tomioka

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Excessive activation of Toll-like receptor 4 (TLR4)/MD-2 by lipopolysaccharide (LPS) causes septic shock. We previously produced an inhibitory antibody, HT52, against LPS-induced human TLR4 activation independently of LPS binding of MD-2. Consistent with the hypothesis that HT52 recognizes the epitopes inherent to inhibitory antibodies, we generated an HT52-crossblockable antibody and revealed the relationship between its inhibitory activity and the anti-TLR4 antibody epitope. Leucine-rich repeat 2 was identified as an inhibitory epitope, and Phe75, Ser76 and Pro79 as antigenic determinants. These findings provide a way to design therapeutic antibodies targeted to TLR4 that are distinct from LPS analog antagonists targeting MD-2.

Original languageEnglish
Pages (from-to)3893-3898
Number of pages6
JournalFEBS Letters
Volume589
Issue number24
DOIs
Publication statusPublished - 2015 Dec 21

Keywords

  • Epitope
  • Inhibitory monoclonal antibody
  • Lipopolysaccharide
  • MD-2
  • Toll-like receptor 4

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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