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PDBsum entry 6dg5
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Biosynthetic protein/protein binding
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PDB id
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6dg5
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Contents |
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93 a.a.
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206 a.a.
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193 a.a.
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References listed in PDB file
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Key reference
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Title
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De novo design of potent and selective mimics of il-2 and il-15.
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Authors
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D.A.Silva,
S.Yu,
U.Y.Ulge,
J.B.Spangler,
K.M.Jude,
C.Labão-Almeida,
L.R.Ali,
A.Quijano-Rubio,
M.Ruterbusch,
I.Leung,
T.Biary,
S.J.Crowley,
E.Marcos,
C.D.Walkey,
B.D.Weitzner,
F.Pardo-Avila,
J.Castellanos,
L.Carter,
L.Stewart,
S.R.Riddell,
M.Pepper,
G.J.L.Bernardes,
M.Dougan,
K.C.Garcia,
D.Baker.
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Ref.
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Nature, 2019,
565,
186-191.
[DOI no: ]
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PubMed id
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Abstract
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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
βγc heterodimer (IL-2Rβγc) 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-2Rβγc 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-2Rβγc, 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.
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