The neuropeptide Y (NPY) system is a multireceptor/multiligand system consisting of four receptors in humans (hY1, hY2, hY4, hY5) and three agonists (NPY, PYY, PP) that activate these receptors with different potency. The relevance of this system in diseases like obesity or cancer, and the different role that each receptor plays influencing different biological processes makes this system suitable for the design of subtype selectivity studies. In this review we focus on the latest findings within the NPY system, we summarize recent mutagenesis studies, structure activity relationship studies, receptor chimera, and selective ligands focusing also on the binding mode of the native agonists.
Background:The Y 4 R is involved in regulation of food intake and gastrointestinal transport. Results: Mutagenesis studies revealed several residues displaying a significant loss of potency for hPP. Conclusion: Tops of TM2, TM6, and TM7 interact with the hY 4 R native agonist hPP. Significance: Characterizing the structure of the Y 4 R binding pocket is crucial for the development of new anti-obesity drugs.
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.
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