8DZ8

Neoleukin 4, a de novo designed IL-4 mimetic

Summary for 8DZ8

• Entry DOI: 10.2210/pdb8dz8/pdb
• Descriptor: neoleukin-4 (1 entity in total)
• Functional Keywords: designed protein, cytokine, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 8
• Total formula weight: 94083.86

Authors

Jude, K.M.,Spangler, J.B.,Garcia, K.C. (deposition date: 2022-08-06, release date: 2023-03-29, Last modification date: 2023-10-25)

Primary citation

Yang, H.,Ulge, U.Y.,Quijano-Rubio, A.,Bernstein, Z.J.,Maestas, D.R.,Chun, J.H.,Wang, W.,Lin, J.X.,Jude, K.M.,Singh, S.,Orcutt-Jahns, B.T.,Li, P.,Mou, J.,Chung, L.,Kuo, Y.H.,Ali, Y.H.,Meyer, A.S.,Grayson, W.L.,Heller, N.M.,Garcia, K.C.,Leonard, W.J.,Silva, D.A.,Elisseeff, J.H.,Baker, D.,Spangler, J.B.
Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds.
Nat.Chem.Biol., 19:1127-1137, 2023

PubMed Abstract: The interleukin-4 (IL-4) cytokine plays a critical role in modulating immune homeostasis. Although there is great interest in harnessing this cytokine as a therapeutic in natural or engineered formats, the clinical potential of native IL-4 is limited by its instability and pleiotropic actions. Here, we design IL-4 cytokine mimetics (denoted Neo-4) based on a de novo engineered IL-2 mimetic scaffold and demonstrate that these cytokines can recapitulate physiological functions of IL-4 in cellular and animal models. In contrast with natural IL-4, Neo-4 is hyperstable and signals exclusively through the type I IL-4 receptor complex, providing previously inaccessible insights into differential IL-4 signaling through type I versus type II receptors. Because of their hyperstability, our computationally designed mimetics can directly incorporate into sophisticated biomaterials that require heat processing, such as three-dimensional-printed scaffolds. Neo-4 should be broadly useful for interrogating IL-4 biology, and the design workflow will inform targeted cytokine therapeutic development.

PubMed: 37024727
DOI: 10.1038/s41589-023-01313-6

Experimental method

X-RAY DIFFRACTION (2.972 Å)