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Deciphering Binding Interactions of IL-23R with HDX-MS: Mapping Protein and Macrocyclic Dodecapeptide Ligands

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journal contribution
posted on 01.08.2018, 00:00 by Cristina Sayago, Isabel C. Gonzalez Valcarcel, Yuewei Qian, John Lee, Jorge Alsina-Fernandez, Nathan C. Fite, Juan J. Carrillo, Feiyu F. Zhang, Michael J. Chalmers, Jeffrey A. Dodge, Howard Broughton, Alfonso Espada
Molecular characterization of the binding epitope of IL-23R and its cognate cytokine IL-23 is paramount to understand the role in autoimmune diseases and to support the discovery of new inhibitors of this protein–protein interaction. Our results revealed that HDX-MS was able to identify the binding epitope of IL-23R:IL-23, which opened the way to evaluate a peptide macrocycle described in the literature as disrupter of this autoimmune target. Thus, the characterization of the interactions of this chemotype by HDX-MS in combination with computational approaches was achieved. To our knowledge, this is the first reported structural evidence regarding the site where a small compound binds to IL-23R.