Interleukin-2 druggability is modulated by global conformational transitions controlled by a helical capping switch
| Autor: | Sgourakis, Jude, Garcia, Nerli, Glassman, Viviane S. De Paula |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Interleukin 2
Receptor complex Magnetic Resonance Spectroscopy medicine.drug_class Protein Conformation drug design medicine.medical_treatment 1.1 Normal biological development and functioning Druggability 010402 general chemistry Monoclonal antibody immunomodulation 01 natural sciences Cell Line 03 medical and health sciences Mice Heterotrimeric G protein medicine Animals Receptor 030304 developmental biology 0303 health sciences Chemistry IL-2 Small molecule NMR 0104 chemical sciences 3. Good health Cytokine 5.1 Pharmaceuticals protein dynamics Biophysics Interleukin-2 Immunization Generic health relevance medicine.drug Biotechnology |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 13 |
| Popis: | Interleukin-2 (IL-2) is a small α-helical cytokine that regulates immune cell homeostasis through its recruitment to a high-affinity heterotrimeric receptor complex (IL-2Rα/IL-2Rβ/γc). IL-2 has been shown to have therapeutic efficacy for immune diseases by preferentially expanding distinct T cell compartments, and several regulatory T cell (Treg)-biasing anti-IL-2 antibodies have been developed for combination therapies. The conformational plasticity of IL-2 plays an important role in its biological actions by modulating the strength of receptor and drug interactions. Through an NMR analysis of milliseconds-timescale dynamics of free mouse IL-2 (mIL-2), we identify a global transition to a sparse conformation which is regulated by an α-helical capping "switch" at the loop between the A and B helices (AB loop). Binding to either an anti-mouse IL-2 monoclonal antibody (mAb) or a small molecule inhibitor near the loop induces a measurable response at the core of the structure, while locking the switch to a single conformation through a designed point mutation leads to a global quenching of core dynamics accompanied by a pronounced effect in mAb binding. By elucidating key details of the long-range allosteric communication between the receptor binding surfaces and the core of the IL-2 structure, our results offer a direct blueprint for designing precision therapeutics targeting a continuum of conformational states. |
| Databáze: | OpenAIRE |
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