Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 13, Pages 7183-7192Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2000419117
Keywords
IL-2; immunomodulation; protein dynamics; NMR; drug design
Categories
Funding
- Howard Hughes Medical Institute
- National Institute of Allergy and Infectious Diseases [R01AI143997, R01AI51321]
- National Institute of General Medical Sciences [R35GM125034]
- National Institute of Diabetes and Digestive and Kidney Diseases [UC4DK116264]
- High End Instrumentation (HIE) [S10OD018455]
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Interleukin-2 (IL-2) is a small a-helical cytokine that regulates immune cell homeostasis through its recruitment to a high-affinity heterotrimeric receptor complex (IL-2R alpha/IL-2R beta/gamma c). IL-2 has been shown to have therapeutic efficacy for immune diseases by preferentially expanding distinct T cell compartments, and several regulatory T cell (T-reg)-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 alpha-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.
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