Neuropeptide Y (NPY) receptors play important roles in appetite regulation. Many efforts have been made to develop drugs to treat obesity by regulating this system. However, the drug discovery is limited by the lack of structural understanding about the distinct recognition patterns between the receptors and their peptide ligands.
In a study published in Science Advances, a team of researchers provide structural and mechanistic insights into NPY signal recognition and transduction by determining the cryo-electron microscopy (cryo-EM) structures of three NPY receptors, Y1R, Y2R, and Y4R, in complex with the NPY peptides and Gi protein.
The groups have focused on structural studies of the NPY receptors for years. They previously solved the crystal structures of Y1R and Y2R bound to different antagonists, which deepened understanding of ligand recognition and subtype selectivity of the NPY receptors. These studies were published in Nature (2018) and Nature Communications (2021).
Combined with mutagenesis, ligand binding, and cell signaling data, the YR-NPY structures reveal interaction details between different NPY receptors and the NPY peptide, and demonstrate that the peptide ligand adopts distinct conformations upon binding to different receptors. This is consistent with the fact that although the NPY receptors share poor sequence identity, they bind NPY with high affinity.
It has been known that the N terminus of the NPY peptide contributes differently to the binding of the peptide to the different NPY receptors, playing a role in subtype selectivity. This is supported by the YR structures, in which the peptide N terminus forms extensive interactions with Y1R, but not with Y2R and Y4R.
Further inspection of the structures revealed that different NPY receptors interact with the middle region of the NPY peptides through different extracellular loops. The receptor extracellular region most likely plays a role in initial ligand recognition, ensuring efficient binding between the receptor and ligand.
In addition, distinct interaction patterns with the last five amino acids at the C terminus of the NPY peptide were observed for different NPY receptors. This region extends into the ligand-binding pocket of the receptor transmembrane domain, leading to conformational changes of the transmembrane helices and subsequent activation of the receptor.
This study uncovers key factors that govern NPY signal recognition and transduction, and would enable development of new anti-obesity drugs with improved efficacy and reduced side effects.
Structures of NPY receptors reveled receptor-specific recognition of NPY peptides
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