4YUE

Mouse IL-2 Bound to S4B6 Fab Fragment

Summary for 4YUE

• Entry DOI: 10.2210/pdb4yue/pdb
• Descriptor: S4B6 Fab heavy chain, S4B6 Fab light chain, Interleukin-2, ... (5 entities in total)
• Functional Keywords: chemokine, antibody, complex, cytokine-immune system complex, cytokine/immune system
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 3
• Total formula weight: 65570.34

Authors

Spangler, J.B.,Jude, K.M.,Garcia, K.C. (deposition date: 2015-03-18, release date: 2015-07-01, Last modification date: 2024-11-06)

Primary citation

Spangler, J.B.,Tomala, J.,Luca, V.C.,Jude, K.M.,Dong, S.,Ring, A.M.,Votavova, P.,Pepper, M.,Kovar, M.,Garcia, K.C.
Antibodies to Interleukin-2 Elicit Selective T Cell Subset Potentiation through Distinct Conformational Mechanisms.
Immunity, 42:815-825, 2015

PubMed Abstract: Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates immune cell homeostasis and has been used to treat a range of disorders including cancer and autoimmune disease. IL-2 signals via interleukin-2 receptor-β (IL-2Rβ):IL-2Rγ heterodimers on cells expressing high (regulatory T cells, Treg) or low (effector cells) amounts of IL-2Rα (CD25). When complexed with IL-2, certain anti-cytokine antibodies preferentially stimulate expansion of Treg (JES6-1) or effector (S4B6) cells, offering a strategy for targeted disease therapy. We found that JES6-1 sterically blocked the IL-2:IL-2Rβ and IL-2:IL-2Rγ interactions, but also allosterically lowered the IL-2:IL-2Rα affinity through a "triggered exchange" mechanism favoring IL-2Rα(hi) Treg cells, creating a positive feedback loop for IL-2Rα(hi) cell activation. Conversely, S4B6 sterically blocked the IL-2:IL-2Rα interaction, while also conformationally stabilizing the IL-2:IL-2Rβ interaction, thus stimulating all IL-2-responsive immune cells, particularly IL-2Rβ(hi) effector cells. These insights provide a molecular blueprint for engineering selectively potentiating therapeutic antibodies.

PubMed: 25992858
DOI: 10.1016/j.immuni.2015.04.015

Experimental method

X-RAY DIFFRACTION (2.194 Å)