20 17 12 1 Science, the top international academic journal, published a research paper on cooperation between the research group of the University of Science and Technology of China and the research group of Wang of Nanjing Agricultural University. This study reveals the near-atomic resolution structure of ATR-ATRIP complex for the first time, reveals the molecular mechanism of ATR kinase activation, and lays a structural foundation for developing new ATR kinase inhibitors for tumor treatment. The result of this research is named. 3.9 ? Structure of yeast Mec 1-Ddc2 complex, human homologue? ATR-ATRIP. Associate Professor Wang Xuejuan is the first author of the paper, and Professor Cai Gang is the correspondent author of the paper.
The maintenance of genome stability is the foundation of all life activities. However, extensive DNA damage and replication pressure caused by various exogenous and endogenous factors constitute the main source of genomic instability. ATR kinase is responsible for initiating the response and repair of cells to genomic instability. Once the DNA damage and replication fork pressure are sensed, ATR kinase will be activated quickly, directly phosphorylating more than 0/000 important substrates (including p53 coding protein, cell cycle regulatory protein, etc.) in the cell. ) and regulate the stability of the genome on a global scale. ATR and its signaling pathway are very important for the stability of genome, the occurrence, development and treatment of tumor. The survival of eukaryotes depends strictly on the activity of ATR kinase, however, the specific molecular mechanism of ATR kinase activation is still unclear.
Genomic instability and mutation is a basic feature of tumor cells, which is usually accompanied by a large number of functional defects in stabilizing and repairing genomic DNA, so cancer cells rely more on ATR kinase. A large number of functional and preclinical experimental data show that ATR kinase inhibitors can directly and efficiently kill tumor cells; In addition, conventional chemotherapy and radiotherapy further aggravate the genomic instability of tumor cells, and inhibiting ATR activity can synergistically enhance the killing activity of conventional tumor therapy on cancer cells. Therefore, ATR kinase inhibitors have important application prospects in cancer treatment. At present, two ATR inhibitors have entered clinical trials, but the specificity and stability of the existing inhibitors need to be strengthened. The development of new ATR inhibitors has important clinical application value and significance in tumor treatment.
Professor Cai Gang's team successfully analyzed the near-atomic resolution (3.9? ) structure, found in cells? ATR exists in the homodimer form of ATR-ATRIP heterodimer. Identify ATR directly related to ATR activation? PRD domain and atrial spiral coil constitute the most important interface between ATR-ATR and ATRIP-ATRIP homologues. PRD and Bridge domains were identified as key regulatory sites of ATR biological function, and it was found that these two key regulatory sites were highly conserved in mTOR, ATM and DNA-PKcs kinases. The activation ring of ATR kinase (activation? Loop) is anchored by its PRD domain through a specific hydrophobic interaction, so it is locked in the state to be activated. ATR-specific activating protein can use its highly conserved hydrophobic residues to competitively release the inhibition of PRD on the activation loop and quickly activate ATR kinase. This achievement not only reveals the molecular mechanism of ATR kinase activation, but also has great scientific significance to help clarify the regulatory mechanism of genome stability. It also reveals that the regulatory sites such as PRD and Bridge on ATR kinase can be used to guide the design of new ATR kinase inhibitors, which provides an important structural basis for the development of new drugs for tumor treatment.
reference data
Biological network. Biological network [citation time 20 17- 12-20]