5E4E

Engineered Interleukin-13 bound to receptor

Summary for 5E4E

• Entry DOI: 10.2210/pdb5e4e/pdb
• Descriptor: Interleukin-13, Interleukin-4 receptor subunit alpha, Interleukin-13 receptor subunit alpha-1, ... (5 entities in total)
• Functional Keywords: agonist-receptor complex, protein engineering, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 73361.29

Authors

Moraga, I.,Thomas, C.,Jude, K.M.,Garcia, K.C. (deposition date: 2015-10-05, release date: 2015-12-02, Last modification date: 2020-07-29)

Primary citation

Moraga, I.,Richter, D.,Wilmes, S.,Winkelmann, H.,Jude, K.,Thomas, C.,Suhoski, M.M.,Engleman, E.G.,Piehler, J.,Garcia, K.C.
Instructive roles for cytokine-receptor binding parameters in determining signaling and functional potency.
Sci.Signal., 8:ra114-ra114, 2015

PubMed Abstract: Cytokines dimerize cell surface receptors to activate signaling and regulate many facets of the immune response. Many cytokines have pleiotropic effects, inducing a spectrum of redundant and distinct effects on different cell types. This pleiotropy has hampered cytokine-based therapies, and the high doses required for treatment often lead to off-target effects, highlighting the need for a more detailed understanding of the parameters controlling cytokine-induced signaling and bioactivities. Using the prototypical cytokine interleukin-13 (IL-13), we explored the interrelationships between receptor binding and a wide range of downstream cellular responses. We applied structure-based engineering to generate IL-13 variants that covered a spectrum of binding strengths for the receptor subunit IL-13Rα1. Engineered IL-13 variants representing a broad range of affinities for the receptor exhibited similar potencies in stimulating the phosphorylation of STAT6 (signal transducer and activator of transcription 6). Delays in the phosphorylation and nuclear translocation of STAT6 were only apparent for those IL-13 variants with markedly reduced affinities for the receptor. From these data, we developed a mechanistic model that quantitatively reproduced the kinetics of STAT6 phosphorylation for the entire spectrum of binding affinities. Receptor endocytosis played a key role in modulating STAT6 activation, whereas the lifetime of receptor-ligand complexes at the plasma membrane determined the potency of the variant for inducing more distal responses. This complex interrelationship between extracellular ligand binding and receptor function provides the foundation for new mechanism-based strategies that determine the optimal cytokine dose to enhance therapeutic efficacy.

PubMed: 26554818
DOI: 10.1126/scisignal.aab2677

Experimental method

X-RAY DIFFRACTION (3 Å)