The Chinese Academy of Sciences announced to the media on August 8 that researchers at the Shanghai Institute of Materia Medica (Shanghai Institute of Materia Medica) recently made an important breakthrough in the field of basic drug research, which can open up a new era for the development of innovative drugs for a series of diseases. ideas and ways.
The drug research paper, jointly led by researchers Xu Huaqiang, Duan Jia and Yang Dehua from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, was recently published in the internationally renowned academic journal Nature. Their international research found the first high-resolution G protein-coupled receptor (GPCR)-neurotensin receptor (NTSR1) complex structure with GPCR kinase (GRK) type 2 (GRK2), revealing that GRK2 Identifying and regulating the detailed molecular mechanism of GPCR, and through structural analysis, discovered a brand-new GPCR-biased ligand-binding pocket for the first time, which opened up a new idea and approach for the clinical development of GPCR-targeting biased drug molecules. Rao Zihe, an academician of the Chinese Academy of Sciences, called it "another milestone achievement in the field of GPCR".
The three most critical scientific issues in the field of GPCR signal transduction. Photo courtesy of Shanghai Institute of Materia Medica, Chinese Academy of Sciences
According to reports, as a type of membrane receptor widely present on human cell membranes, GPCRs are important regulators of cell signal transduction, which participate in the regulation of almost all life in the human body In the process of activity, from chemical perception, including vision, smell, and taste, to regulation related to endocrine molecules, including neurotransmission, immune regulation, and metabolic regulation, the human genome can encode more than 800 GPCRs. At present, about one-third of the clinical drugs approved for marketing act on GPCR to play a therapeutic role. GPCR is considered to be the most important and one of the most promising drug targets in the field of new drug research and development.
In this study, Duan Jia's research team finally successfully analyzed the first high-resolution GPCR-GRK2 complex structure through a series of technical means. Combined with mutation experiments at the cellular level, the detailed molecular mechanism of GRK2 recognizing and regulating NTSR1 was elucidated for the first time. These findings represent another major breakthrough in the field of GPCR signaling and have the potential to improve drug development to improve patient outcomes. This study provides a detailed structural analysis of the interaction between neurotensin receptors NTSR1, GRK2 and a biased ligand (SBI-553), laying the structural foundation for the development of new drugs that target GPCRs more precisely and with better effects , which has great significance for the development of innovative drugs for the treatment of a range of diseases, including cancer, cardiovascular diseases and neurological diseases.
Xu Huaqiang's research team has been focusing on the structural analysis and functional research of biological macromolecular complexes for a long time, especially in the research of GPCR signal transduction complexes. On the basis of ten years of research, through the further development of a series of advanced technical means, the high-resolution GPCR-GRK complex structure was successfully analyzed for the first time, revealing one of the most critical scientific issues in the field of GPCR signal transduction, that is, how GPCR is recognized by GRK and regulation. At the same time, the various technical methods used in this study combined with single-particle cryo-electron microscopy will also provide important inspiration and guidance for the future study of other biological multivariate dynamic complexes, thereby promoting the development of the entire biological macromolecular multivariate dynamic complex research. process.
NTSR1-GRK2 structural features. Photo provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences
According to the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, this study revealed for the first time that SBI-553 binds to the hydrophobic pocket inside the receptor cell, which is different from all previous small molecule binding pockets , which opens up a new idea and approach for the development of new biased drugs targeting GPCRs in the future. In addition, this study also elucidated for the first time the structural mechanism of SBI-553 to realize the biased activation of the receptor (arrestin) pathway, which, combined with Xu Huaqiang's research team's earlier discovery of the mechanism of action of G protein biased ligands, greatly promotes the academic community's understanding of The understanding of GPCR-biased signal transduction lays a solid foundation for the development of GPCR-targeted drug molecules in the future.
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