More than 2.2 billion people worldwide are overweight or obese, which is a serious global public health problem, according to the World Health Organization. However, few weight loss-drugs can achieve the effect by surgical treatment for losing weight due to drug's low efficacy and poor safety. Therefore, developing new weight loss drugs with high efficacy and good safety has been a hot issue with difficulty in the sector of obesity treatment.
Neuropeptide Y (NPY) receptor is one of the G protein-coupled receptors (GPCR). Meanwhile, there are four NPY receptors (Y1R, Y2R, Y4R and Y5R) in human body. These NPY receptors play a significant role in regulating life activities such as food intake and energy consumption by binding to the three NPY polypeptide ligands (NPY, PYY and PP), and are targets of anti-obesity drugs with great concern. However, the complicated regulation mechanism of NPY receptor-NPY system makes the development of drugs targeting such receptors challenging, and there are no relevant drugs on sale in market.
Prof. Wu Beili workshop of the School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Zhao Qiang's research group of Shanghai Institute of Materia Medica, Annette G. Beck-Sickinger and Anette Kaiser research groups from the University of Leipzig have made great strides in the research of structure and function of NPY receptor. The group succeeded in analyzing the structure of the complex of Y1R, Y2R and Y4R bound to NPY polypeptides and Gi proteins respectively, and shed light on the ligand recognition models and signal transduction mechanisms of these receptors. The research is of great significance for a comprehensive understanding of NPY receptors' molecular mechanism such as physiological and pathological functions and promoting the R & D of anti-obesity drugs. The relevant research was published inScience Advances,an international top academic journal, under the title of Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors on May 5, 2022 (Beijing time).
This studyfirst expounds the fine binding modes and ligand selection mechanisms between different NPY receptors and natural polypeptide agonists and reveals the activation mechanism of receptors, providing an important basis for better understanding of the cellular signal transduction mechanism of these receptors, which will boost the R & D of anti-obesity drugs.
The similarity of amino acid sequence in different NPY receptors is low, but these receptors can recognize and bind NPY polypeptide ligands, indicating that these receptors have specific and diverse recognition mechanisms for cellular signaling. Based on the structural information, researchers elucidated the fine binding modes between different NPY receptors and NPY peptide ligands by using various research methods such as amino acid mutation, receptor-ligand binding and cellular signal transduction. At the same time, they also found that NPY peptides can be bound to different receptors by regulating their own special conformation.
Previous studies have shown that the N-terminal region of NPY polypeptides plays a different role in identifying different NPY receptors, but the role of identifying the molecular mechanisms is unclear. The structure of complex ofY1R, Y2R and Y4R with NPY polypeptides shows that the N-terminal region of NPY and Y1R are close, but the force of N-terminal with Y2R and Y4R is not strong. Because the non-conservation of amino acids at the binding site causes these differences.
In addition, the extracellular ring region of receptors also have great impacts on the specific recognition of NPY-like polypeptides, and various NPY receptors interact with NPY polypeptides through different extracellular ring and the middle region of NPY polypeptides. The early stage of receptor-peptide ligand recognition was taken place in this region, ensuring efficient receptor-ligand recognition and binding. The five amino acids at the C-terminal of the NPY polypeptide are key regions of binding to the NPY receptors. Because the region can extend into the ligand-binding region in the receptor's transmembrane domain and cause conformational changes in the transmembrane helix, leading to receptor activation. Although this segment is consistent with the binding sites in Y1R, Y2R and Y4R, its modes of action with different receptors varies greatly, and receptors are activated by the formation of force with various amino acids. Schematic diagram of structure of Neuropeptide Y receptors.
Neuropeptide Y receptors involved in regulating food intake and energy consumption are important targets of obesity therapeutic drugs. The structures of complex of Y1R, Y2R and Y4R binding to NPY peptides and G proteins are shown from left to right.The Y1R, Y2R and Y4R receptors are shown in dark blue, orange and light blue, and the natural ligand NPY bound to Y1R and Y2R is shown in purple and green in the diagram, while the natural ligand PP bound to Y4R is shown in yellow.
These fine modes of action provide an important structural basis for the design of highly specific ligand molecules, which will make contributions to new anti-obesity drugs with better efficacy and fewer side effects.
Theco-first authors of this paper areTang Tingting, a postdoctoral fellow ofSchool of Pharmaceutical Science and Technology (with Hangzhou Institute for Advanced Study, UCAS as the first signatory), associate research fellows Tan Qiuxiang and Han Shuo from the Shanghai Institute of Materia Medica, doctoral student Anne Diemar from the University of Leipzig. The corresponding authors of this study areWu Beili, Chief Professor of theSchool of Pharmaceutical Science and Technology, Zhao Qiang, a research fellow of Shanghai Institute of Materia Medica, and Professor Annette G. Beck-Sickinger and Professor Anette Kaiser from the University of Leipzig, Germany. The research was funded by some organizations such as National Natural Science Foundation of China, the Ministry of Science and Technology of the People's Republic of China, Science and Technology Commission of Shanghai Municipality, the Chinese Academy of Sciences, and Deutsche Forschungsgemeinschaft (DFG).
Article link: https://www.science.org/doi/10.1126/science.ada1232
Source |School of Pharmaceutical Science and Technology
Typesetter | Liu Yuqi
Executive Editor | Wang Xia
Published in Zhejiang
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