The inflammatory chemokine CCL5, which binds the chemokine receptor CCR5 in a two-step mechanism so as to activate signaling pathways in hematopoetic cells, plays an important role in immune surveillance, inflammation, and development as well as in several immune system pathologies. The recently published crystal structure of CCR5 bound to a high-affinity variant of CCL5 lacks the N-terminal segment of the receptor that is post-translationally sulfated and is known to be important for high-affinity binding. Here, we report the NMR solution structure of monomeric CCL5 bound to a synthetic doubly sulfated peptide corresponding to the missing first 27 residues of CCR5. Our structures show that two sulfated tyrosine residues, sY10 and sY14, as well as the unsulfated Y15 form a network of strong interactions with a groove on a surface of CCL5 that is formed from evolutionarily conserved basic and hydrophobic amino acids. We then use our NMR structures, in combination with available crystal data, to create an atomic model of full-length wild-type CCR5:CCL5. Our findings reveal the structural determinants involved in the recognition of CCL5 by the CCR5 N terminus. These findings, together with existing structural data, provide a complete structural framework with which to understand the specificity of receptor:chemokine interactions. Database: Structural data are available in the PDB under the accession number 6FGP.
Bibliographical noteFunding Information:
The authors thank Dr. Tali Scherf for help in setting up some of the NMR experiments. This study was supported by the Minerva Foundation with funding from the Federal German Ministry for Education and Research, by the US-Israel Binational Science Foundation by the Comisaroff Family Trust, The estate of D. Levinson and by the Kimmelman Center (JA), by the National Institutes of Health USA (R35GM122543 to ML), and by a Niels Stensen postdoctoral fellowship (JR). JA is the Dr. Joseph and Ruth Owades Professor of Chemistry. FN was supported by the Erna and Jakob Michael Visiting Professorship while on Sabbatical at the Weizmann Institute of Science.
© 2018 Federation of European Biochemical Societies
- chemokine receptors
- intermolecular interactions
- protein complexes
- sulfated tyrosine
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology