Interleukin-2 druggability is modulated by global conformational transitions controlled by a helical capping switch
Open Access
- 17 March 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (13), 7183-7192
- https://doi.org/10.1073/pnas.2000419117
Abstract
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.Funding Information
- HHS | NIH | National Institute of General Medical Sciences (5R35GM125034)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (5R01AI143997)
- HHS | NIH | NIH Office of the Director (S10OD018455)
This publication has 34 references indexed in Scilit:
- Antibodies to Interleukin-2 Elicit Selective T Cell Subset Potentiation through Distinct Conformational MechanismsImmunity, 2015
- Interleukin-2 at the Crossroads of Effector Responses, Tolerance, and ImmunotherapyImmunity, 2013
- Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’Nature, 2012
- The role of interleukin-2 during homeostasis and activation of the immune systemNature Reviews Immunology, 2012
- Interleukin-2 Receptor Signaling: At the Interface between Tolerance and ImmunityImmunity, 2010
- IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor α subunit CD25Proceedings of the National Academy of Sciences of the United States of America, 2010
- Hot-spot mimicry of a cytokine receptor by a small moleculeProceedings of the National Academy of Sciences of the United States of America, 2006
- Tolerance, not immunity, crucially depends on IL-2Nature Reviews Immunology, 2004
- Binding of small molecules to an adaptive protein–protein interfaceProceedings of the National Academy of Sciences of the United States of America, 2003
- The IL-2/IL-2 receptor system: A current overviewCell, 1993