Interleukin-2 druggability is modulated by global conformational transitions controlled by a helical capping switch
Interleukin-2 druggability is modulated by global conformational transitions controlled by a helical capping switch
SUMMARY 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 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 a NMR analysis of milliseconds-timescale dynamics of free mIL-2 we identify a global transition to an auto-inhibitory conformation controlled by an α-helical capping “switch”. Binding to either an anti-mouse IL-2 mAb or a small molecule inhibitor near the AB loop induces changes in dynamics at the core of the structure, and perturbations of the capping hydrogen-bond network abrogate Ab binding by destabilizing the auto-inhibitory conformation. Our results highlight a paradigm for designing precision therapeutics targeting a continuum of IL-2 conformational states.
De Paula Viviane S.、Nerli Santrupti、Glassman Caleb R.、Garcia K. Christopher、Jude Kevin M.、Sgourakis Nikolaos G.
Department of Chemistry and Biochemistry, University of California Santa CruzDepartment of Computer Science, University of California Santa CruzHoward Hughes Medical Institute, Stanford University School of Medicine||Department of Molecular and Cellular Physiology, Stanford University School of Medicine||Department of Structural Biology, Stanford University School of MedicineHoward Hughes Medical Institute, Stanford University School of Medicine||Department of Molecular and Cellular Physiology, Stanford University School of Medicine||Department of Structural Biology, Stanford University School of MedicineHoward Hughes Medical Institute, Stanford University School of Medicine||Department of Molecular and Cellular Physiology, Stanford University School of Medicine||Department of Structural Biology, Stanford University School of MedicineDepartment of Chemistry and Biochemistry, University of California Santa Cruz
基础医学生物化学分子生物学
De Paula Viviane S.,Nerli Santrupti,Glassman Caleb R.,Garcia K. Christopher,Jude Kevin M.,Sgourakis Nikolaos G..Interleukin-2 druggability is modulated by global conformational transitions controlled by a helical capping switch[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/821207.点此复制
评论