6dg5 | pdb_00006dg5
Structure of a de novo designed Interleukin-2/Interleukin-15 mimetic complex with IL-2Rb and IL-2Rg
Structural highlights
FunctionIL2RB_MOUSE Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2. Publication Abstract from PubMedWe 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 betagammac heterodimer (IL-2Rbetagammac) but have no binding site for IL-2Ralpha (also called CD25) or IL-15Ralpha (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rbetagammac with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Ralpha and IL-15Ralpha. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rbetagammac, 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. De novo design of potent and selective mimics of IL-2 and IL-15.,Silva DA, Yu S, Ulge UY, Spangler JB, Jude KM, Labao-Almeida C, Ali LR, Quijano-Rubio A, Ruterbusch M, Leung I, Biary T, Crowley SJ, Marcos E, Walkey CD, Weitzner BD, Pardo-Avila F, Castellanos J, Carter L, Stewart L, Riddell SR, Pepper M, Bernardes GJL, Dougan M, Garcia KC, Baker D Nature. 2019 Jan;565(7738):186-191. doi: 10.1038/s41586-018-0830-7. Epub 2019 Jan, 9. PMID:30626941[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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