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Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand
IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Rα and gp130. Because of its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOM...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961693/ https://www.ncbi.nlm.nih.gov/pubmed/24415767 http://dx.doi.org/10.1074/jbc.M113.532697 |
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author | Gelinas, Amy D. Davies, Douglas R. Edwards, Thomas E. Rohloff, John C. Carter, Jeffrey D. Zhang, Chi Gupta, Shashi Ishikawa, Yuichi Hirota, Masao Nakaishi, Yuichiro Jarvis, Thale C. Janjic, Nebojsa |
author_facet | Gelinas, Amy D. Davies, Douglas R. Edwards, Thomas E. Rohloff, John C. Carter, Jeffrey D. Zhang, Chi Gupta, Shashi Ishikawa, Yuichi Hirota, Masao Nakaishi, Yuichiro Jarvis, Thale C. Janjic, Nebojsa |
author_sort | Gelinas, Amy D. |
collection | PubMed |
description | IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Rα and gp130. Because of its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (S low Off-rate Modified Aptamers) that bind IL-6 and inhibit its biologic activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here, we report the co-crystal structure of a high affinity SOMAmer (K(d) = 0.20 nm) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Rα and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (K(d) = 270 nm). A single substitution from our diversely modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (K(d) = 7.4 nm). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer·IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets. |
format | Online Article Text |
id | pubmed-3961693 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-39616932014-03-25 Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand Gelinas, Amy D. Davies, Douglas R. Edwards, Thomas E. Rohloff, John C. Carter, Jeffrey D. Zhang, Chi Gupta, Shashi Ishikawa, Yuichi Hirota, Masao Nakaishi, Yuichiro Jarvis, Thale C. Janjic, Nebojsa J Biol Chem Protein Structure and Folding IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Rα and gp130. Because of its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (S low Off-rate Modified Aptamers) that bind IL-6 and inhibit its biologic activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here, we report the co-crystal structure of a high affinity SOMAmer (K(d) = 0.20 nm) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Rα and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (K(d) = 270 nm). A single substitution from our diversely modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (K(d) = 7.4 nm). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer·IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets. American Society for Biochemistry and Molecular Biology 2014-03-21 2014-01-12 /pmc/articles/PMC3961693/ /pubmed/24415767 http://dx.doi.org/10.1074/jbc.M113.532697 Text en © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/) applies to Author Choice Articles |
spellingShingle | Protein Structure and Folding Gelinas, Amy D. Davies, Douglas R. Edwards, Thomas E. Rohloff, John C. Carter, Jeffrey D. Zhang, Chi Gupta, Shashi Ishikawa, Yuichi Hirota, Masao Nakaishi, Yuichiro Jarvis, Thale C. Janjic, Nebojsa Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand |
title | Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand |
title_full | Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand |
title_fullStr | Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand |
title_full_unstemmed | Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand |
title_short | Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand |
title_sort | crystal structure of interleukin-6 in complex with a modified nucleic acid ligand |
topic | Protein Structure and Folding |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961693/ https://www.ncbi.nlm.nih.gov/pubmed/24415767 http://dx.doi.org/10.1074/jbc.M113.532697 |
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