Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies - Architecture et Fonction des Macromolécules Biologiques
Article Dans Une Revue Journal of Biological Chemistry Année : 2016

Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies

Christophe Blanchetot
  • Fonction : Auteur
Natalie de Jonge
  • Fonction : Auteur
Nico Ongenae
  • Fonction : Auteur
Erik Hofman
  • Fonction : Auteur
Alex Klarenbeek
  • Fonction : Auteur
Ava Sadi
  • Fonction : Auteur
Anna Hultberg
  • Fonction : Auteur
Anke Kretz-Rommel
  • Fonction : Auteur
Remy Loris
Hans De Haard
  • Fonction : Auteur

Résumé

Interleukin 6 plays a key role in mediating inflammatory reac- tions in autoimmune diseases and cancer, where it is also involved in metastasis and tissue invasion. Neutralizing anti- bodies against IL-6 and its receptor have been approved for ther- apeutic intervention or are in advanced stages of clinical devel- opment. Here we describe the crystal structures of the complexes of IL-6 with two Fabs derived from conventional camelid antibodies that antagonize the interaction between the cytokine and its receptor. The x-ray structures of these com- plexes provide insights into the mechanism of neutralization by the two antibodies and explain the very high potency of one of the antibodies. It effectively competes for binding to the cyto- kine with IL-6 receptor (IL-6R) by using side chains of two CDR residues filling the site I cavities of IL-6, thus mimicking the interactions of Phe229 and Phe279 of IL-6R. In the first antibody, a HCDR3 tryptophan binds similarly to hot spot residue Phe279 . Mutation of this HCDR3 Trp residue into any other residue except Tyr or Phe significantly weakens binding of the antibody to IL-6, as was also observed for IL-6R mutants of Phe279 . In the second antibody, the side chain of HCDR3 valine ties into site I like IL-6R Phe279 , whereas a LCDR1 tyrosine side chain occupies a second cavity within site I and mimics the interactions of IL-6R Phe229
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hal-01439109 , version 1 (11-07-2024)

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Christophe Blanchetot, Natalie de Jonge, Aline Desmyter, Nico Ongenae, Erik Hofman, et al.. Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies. Journal of Biological Chemistry, 2016, 291 (26), pp.13846-13854. ⟨10.1074/jbc.M115.695528⟩. ⟨hal-01439109⟩
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