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Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies
Interleukin 6 plays a key role in mediating inflammatory reactions in autoimmune diseases and cancer, where it is also involved in metastasis and tissue invasion. Neutralizing antibodies against IL-6 and its receptor have been approved for therapeutic intervention or are in advanced stages of clinic...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919466/ https://www.ncbi.nlm.nih.gov/pubmed/27129274 http://dx.doi.org/10.1074/jbc.M115.695528 |
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author | Blanchetot, Christophe De Jonge, Natalie Desmyter, Aline Ongenae, Nico Hofman, Erik Klarenbeek, Alex Sadi, Ava Hultberg, Anna Kretz-Rommel, Anke Spinelli, Silvia Loris, Remy Cambillau, Christian de Haard, Hans |
author_facet | Blanchetot, Christophe De Jonge, Natalie Desmyter, Aline Ongenae, Nico Hofman, Erik Klarenbeek, Alex Sadi, Ava Hultberg, Anna Kretz-Rommel, Anke Spinelli, Silvia Loris, Remy Cambillau, Christian de Haard, Hans |
author_sort | Blanchetot, Christophe |
collection | PubMed |
description | Interleukin 6 plays a key role in mediating inflammatory reactions in autoimmune diseases and cancer, where it is also involved in metastasis and tissue invasion. Neutralizing antibodies against IL-6 and its receptor have been approved for therapeutic intervention or are in advanced stages of clinical development. 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 complexes 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 cytokine 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 Phe(229) and Phe(279) of IL-6R. In the first antibody, a HCDR3 tryptophan binds similarly to hot spot residue Phe(279). 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 Phe(279). In the second antibody, the side chain of HCDR3 valine ties into site I like IL-6R Phe(279), whereas a LCDR1 tyrosine side chain occupies a second cavity within site I and mimics the interactions of IL-6R Phe(229). |
format | Online Article Text |
id | pubmed-4919466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-49194662016-07-08 Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies Blanchetot, Christophe De Jonge, Natalie Desmyter, Aline Ongenae, Nico Hofman, Erik Klarenbeek, Alex Sadi, Ava Hultberg, Anna Kretz-Rommel, Anke Spinelli, Silvia Loris, Remy Cambillau, Christian de Haard, Hans J Biol Chem Immunology Interleukin 6 plays a key role in mediating inflammatory reactions in autoimmune diseases and cancer, where it is also involved in metastasis and tissue invasion. Neutralizing antibodies against IL-6 and its receptor have been approved for therapeutic intervention or are in advanced stages of clinical development. 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 complexes 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 cytokine 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 Phe(229) and Phe(279) of IL-6R. In the first antibody, a HCDR3 tryptophan binds similarly to hot spot residue Phe(279). 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 Phe(279). In the second antibody, the side chain of HCDR3 valine ties into site I like IL-6R Phe(279), whereas a LCDR1 tyrosine side chain occupies a second cavity within site I and mimics the interactions of IL-6R Phe(229). American Society for Biochemistry and Molecular Biology 2016-06-24 2016-04-27 /pmc/articles/PMC4919466/ /pubmed/27129274 http://dx.doi.org/10.1074/jbc.M115.695528 Text en © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) . |
spellingShingle | Immunology Blanchetot, Christophe De Jonge, Natalie Desmyter, Aline Ongenae, Nico Hofman, Erik Klarenbeek, Alex Sadi, Ava Hultberg, Anna Kretz-Rommel, Anke Spinelli, Silvia Loris, Remy Cambillau, Christian de Haard, Hans Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies |
title | Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies |
title_full | Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies |
title_fullStr | Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies |
title_full_unstemmed | Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies |
title_short | Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies |
title_sort | structural mimicry of receptor interaction by antagonistic interleukin-6 (il-6) antibodies |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919466/ https://www.ncbi.nlm.nih.gov/pubmed/27129274 http://dx.doi.org/10.1074/jbc.M115.695528 |
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