ArticleProceedings of the National Academy of Sciences of the United States of America1997
A mixed-charge pair in human interleukin 4 dominates high-affinity interaction with the receptor alpha chain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1997. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 96 citations in OpenAlex.
- Lymphocytes and monocytes undergo swift suppression of IL-10R, IL-6R, and IL-2Rβγ signaling under high concentrations of different cytokines.bioRxiv : the preprint server for biology · 2025Article
- MuToN Quantifies Binding Affinity Changes upon Protein Mutations by Geometric Deep Learning.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Insights into receptor structure and dynamics at the surface of living cells.Nature communications · 2023Article
- Improve hot region prediction by analyzing different machine learning algorithms.BMC bioinformatics · 2021Article
- Assessment of software methods for estimating protein-protein relative binding affinities.PloS one · 2020Article
- Rate Constants and Mechanisms of Protein-Ligand Binding.Annual review of biophysics · 2017Review
- Dynamics and interaction of interleukin-4 receptor subunits in living cells.Biophysical journal · 2014Article
- Electrostatic interactions in the binding pathway of a transient protein complex studied by NMR and isothermal titration calorimetry.The Journal of biological chemistry · 2014Article
- Structural insights into the common γ-chain family of cytokines and receptors from the interleukin-7 pathway.Immunological reviews · 2012Review
- Regulation of inflammation by interleukin-4: a review of "alternatives".Journal of leukocyte biology · 2012Review
- Single cell analysis of ligand binding and complex formation of interleukin-4 receptor subunits.Biophysical journal · 2011Article
- Rationalizing 5000-fold differences in receptor-binding rate constants of four cytokines.Biophysical journal · 2011Article
- Charged residues at protein interaction interfaces: unexpected conservation and orchestrated divergence.Protein science : a publication of the Protein Society · 2011Article
- Article
- Predictions of hot spot residues at protein-protein interfaces using support vector machines.PloS one · 2011Article
- Ways and means of coping with uncertainties of the relationship of the genetic blue print to protein structure and function in the cell.Cell communication and signaling : CCS · 2010Article
- Diversifying selection and functional analysis of interleukin-4 suggests antagonism-driven evolution at receptor-binding interfaces.BMC evolutionary biology · 2010Article
- Rational design of interleukin-21 antagonist through selective elimination of the gammaC binding epitope.The Journal of biological chemistry · 2010Article
- Contribution of asparagine residues to the stabilization of a proteinaceous antigen-antibody complex, HyHEL-10-hen egg white lysozyme.The Journal of biological chemistry · 2010Article
- Structural biology of shared cytokine receptors.Annual review of immunology · 2009Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human interleukin 4 (IL-4) binds to its cellular receptor with a Kd in the subnanomolar range, similar to many other 4-helix-bundle proteins interacting with members of the hematopoietin (cytokine) receptor superfamily. In the IL-4 system this interaction is predominantly determined by the extracellular domain (IL4-BP) of the receptor alpha chain (Kd approximately 150 pM). Now a high-resolution mutational and kinetic analysis has revealed that the high-affinity binding of IL-4 originates from a continuous patch of a few mostly polar or charged amino acid side chains located on helices A and C. The binding epitope comprises (i) a set of side chains determining the dissociation rate (k(off)) and (ii) a partially overlapping set determining the association rate constant (k(on)) of the IL-4/IL4-BP complex. The k(off) epitope is assembled from two juxtaposed main determinants (Glu-9 and Arg-88) surrounded by five side chains (Ile-5, Thr-13, Arg-53, Asn-89, and Trp-91) of lower importance. The cumulative increase in k(off) after alanine substitution is 10(5)-fold for the central mixed-charge pair and 3 x 10(3)-fold for the satellites. The k(on) epitope is formed by five positively charged residues on helix C (Lys-77, Arg-81, Lys-84, Arg-85, and Arg-88) and two neighboring residues on helix A (Glu-9 and Thr-13). The cumulative loss in k(on) of the alanine variants is only about 10-fold. These results provide the basis for an understanding of molecular recognition in cytokine receptor complexes and for an IL-4 antagonist design.
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