New progress has been made in the field of transcription factor drug targets

Physiological functions of NPAS4 (A), related diseases (B) and protein dimer structure (C) Courtesy of Shandong University

Recently, the research group of Professor Wu Dalei of the State Key Laboratory of Microbial Technology of Shandong University published new results online in the Proceedings of the National Academy of Sciences, making new progress in the field of transcription factor drug targets.

Neuronal PAS domain protein 4 (NPAS4) is a transcription factor mainly distributed in the brain, belonging to the “nuclear receptor” bHLH-PAS (basic loop-helix-loop PER-ARNT-SIM) transcription factor family, involved in regulating a series of downstream gene expression related to brain cognition and memory, which can maintain the excited-inhibitory balance of neural circuits.

In addition to nerve cells, NPAS4 is also present in pancreatic islet and vascular epithelial cells. NPAS4 dysfunction is associated with neurodevelopmental disorders such as depression, schizophrenia, and autism. Therefore, it is a potential new target for the treatment of these neuropsychiatric diseases, and it is also expected to be a potential drug target related to type II diabetes, pancreas transplantation and angiogenesis.

In this study, the complex structure of NPAS4 and two dimeric partner proteins and DNA was analyzed for the first time, the unique structure of the NPAS4 subunit was visualized, and the different dimerization modes of NPAS4-ARNT and NPAS4-ARNT2 were displayed. It was found that ARNTs bind NPAS4 differently from other members of the bHLH-PAS family, expanding our understanding of heterodimericization patterns in this family.

According to reports, in view of the close connection between NPAS4 and human diseases, its structural elucidation has laid the foundation for the future discovery of drugs targeting NPAS4.

The main research areas of Wu Dalei’s research group are the structure and function of transcription factor target proteins and related drug discovery, and also carry out structural elucidation and catalytic mechanism research of biosynthesis-related enzymes. This research work was supported by the Shandong Outstanding Youth Fund, the National Natural Science Foundation of China, Young Taishan Scholars and Shandong University Youth Interdisciplinary Scientific Innovation Group. The public technology platform for life environment research of Shandong University, the National Protein Science Research (Shanghai) Facility and the Shanghai Synchrotron Radiation Light Source provided important support for this work. (Source: China Science News, Liao Yang, Che Huiqing)

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