Cyclic Analogues of the Chemerin C‑Terminus Mimic a Loop Conformation Essential for Activating the Chemokine-like Receptor 1

The chemokine-like receptor 1 (CMKLR1)
is a promising target for
treating autoinflammatory diseases, cancer, and reproductive disorders.
However, the interaction between CMKLR1 and its protein–ligand
chemerin remains uncharacterized, and no drugs targeting this interaction
have passed clinical trials. Here, we identify the binding mode of
chemerin-9, the C-terminus of chemerin, at the receptor by combining
complementary mutagenesis with structure-based modeling. Incorporating
our experimental data, we present a detailed model of this binding
site, including experimentally confirmed pairwise interactions for
the most critical ligand residues: Chemerin-9 residue F8 binds to a hydrophobic pocket in CMKLR1 formed by the extracellular
loop (ECL) 2, while F6 interacts with Y2.68,
suggesting a turn-like structure. On the basis of this model, we created
the first cyclic peptide with nanomolar activity, confirming the overall
binding conformation. This constrained agonist mimics the loop conformation
adopted by the natural ligand and can serve as a lead compound for
future drug design.