6DG6

Structure of a de novo designed Interleukin-2/Interleukin-15 mimetic

Summary for 6DG6

• Entry DOI: 10.2210/pdb6dg6/pdb
• Descriptor: Neoleukin-2/15 (2 entities in total)
• Functional Keywords: cytokine mimetic, biosynthetic protein
• Biological source: synthetic construct
• Total number of polymer chains: 6
• Total formula weight: 72677.03

Authors

Jude, K.M.,Silva, D.-A.,Yu, S.,Baker, D.,Garcia, K.C. (deposition date: 2018-05-16, release date: 2019-01-16, Last modification date: 2024-04-03)

Primary citation

Silva, D.A.,Yu, S.,Ulge, U.Y.,Spangler, J.B.,Jude, K.M.,Labao-Almeida, C.,Ali, L.R.,Quijano-Rubio, A.,Ruterbusch, M.,Leung, I.,Biary, T.,Crowley, S.J.,Marcos, E.,Walkey, C.D.,Weitzner, B.D.,Pardo-Avila, F.,Castellanos, J.,Carter, L.,Stewart, L.,Riddell, S.R.,Pepper, M.,Bernardes, G.J.L.,Dougan, M.,Garcia, K.C.,Baker, D.
De novo design of potent and selective mimics of IL-2 and IL-15.
Nature, 565:186-191, 2019

PubMed Abstract: We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor βγ heterodimer (IL-2Rβγ) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rβγ with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rβγ, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.

PubMed: 30626941
DOI: 10.1038/s41586-018-0830-7

Experimental method

X-RAY DIFFRACTION (1.999 Å)