Structural Basis of Receptor Sulfotyrosine Recognition by a CC Chemokine: The N-Terminal Region of CCR3 Bound to CCL11/Eotaxin-1
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Trafficking of leukocytes in immune surveillance and inflammatory responses is activated by chemokines engaging their receptors. Sulfation of tyrosine residues in peptides derived from the eosinophil chemokine receptor CCR3 dramatically enhances binding to cognate chemokines. We report the structural basis of this recognition and affinity enhancement. We describe the structure of a CC chemokine (CCL11/eotaxin-1) bound to a fragment of a chemokine receptor: residues 8–23 of CCR3, including two sulfotyrosine residues. We also show that intact CCR3 is sulfated and sulfation enhances receptor activity. The CCR3 sulfotyrosine residues form hydrophobic, salt bridge and cation-p interactions with residues that are highly conserved in CC chemokines. However, the orientation of the chemokine relative to the receptor N terminus differs substantially from those observed for two CXC chemokines, suggesting that initial binding of the receptor sulfotyrosine residues guides subsequent steps in receptor activation, thereby influencing the receptor conformational changes and signaling.
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The N-terminal region of eotaxin-1 plays a critical role in binding and activation of its receptor CCR3.
“Recent structural studies have implicated a critical role for this region of eotaxin-1 in binding and activation of its receptor CCR3.45”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [45]
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- Authors
- Millard, C. J., Ludeman, J. P., Canals, M., Bridgford, J. L., Hinds, M. G., Clayton, D. J., Christopoulos, A., Payne, R. J., & Stone, M. J.
- Affiliations
- Monash University (AU)
- The University of Melbourne (AU)
- The University of Sydney (AU)
- Corresponding author
- Stone, Martin J.
- ORCID
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 22
- Issue
- 11
- Pages
- 1571-1581
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2077748569
- Cited by
- 75
- References
- 55
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 8 · 2017: 14 · 2016: 7 · 2015: 10 · 2014: 2
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Repository@Nottingham (University of Nottingham) (submittedVersion)
- Funders
- Servier
- Medical Research Council
- Australian Research Council (DP1094884, DP130101984, LE0989504, DP0881570)
- National Health and Medical Research Council
- National Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- CCR3, CC chemokines, chemokine receptor binding, tyrosine sulfation, salt bridges, receptor activation, receptor conformational change
- MeSH terms
- Amino Acid Sequence, Binding Sites, Humans, Models, Molecular, Magnetic Resonance Spectroscopy, Tyrosine, Conserved Sequence, Protein Structure, Secondary, Receptors, CCR3, Chemokine CCL11, HEK293 Cells
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