A team of researchers led by a science couple Cai Gang and Wang Xuejuan from the University of Science and Technology of China becomes the first to determine the structure of the ATR-ATRIP complex in near-atomic detail, which reveals the regulatory mechanism of ATR activity and may shed lights on future cancer therapy. On Dec 1st, the related study was published in the journal Science.
The ATR protein is the apical kinase to cope with the prevalent single strand DNA breaks and DNA replication stress. The ATR signaling abnormalities disturb cell viability and cause clinically distinct disorders including several kinds of cancers. In vivo, the ATR activity must be tightly regulated to maintain cellular homeostasis. Upon DNA damage, the ATR should be immediately activated; whereas, accidental ATR activation in the absence of DNA damage could induce cell death.
It has long been a central question to determine activation mechanism of ATR kinase -how it responds to DNA damage and how it is activated. To learn more about the detailed architecture of the ATR-ATRIP complex and possible ways to therapeutically target it, Dr. Cai, Dr. Wang and their colleagues used cryo-electron microscopy (cryo-EM) to analyze the yeast ATR-ATRIP complex and produced the crystal clear, three-dimensional structure at near-atomic resolution.
The 3.9 Å structure shows ATR-ATRIP forms a dimer of heterodimers and illuminates critical regulatory sites of the ATR kinase, which is poised for catalysis due to the activation loop is immobilized. Upon DNA damage, specific ATR activators could immediately release the inhibition on the activation loop and culminate in full ATR kinase activity.
Artist's concept of launching the cellular DNA-damage response by the ATR-ATRIP complex./Image by WANG Guoyan & CHEN Lei.
Owing to its pivotal roles in the regulation of genomic integrity, ATR has been a potentially viable therapeutic target. Preclinical evidence shows that ATR inhibitors do indeed substantially enhance the efficacy of both conventional chemotherapy and radiotherapy, and several agents have recently entered clinical trials.
Development of more specific and efficient ATR inhibitors holds the promise for significant cancer treatment improvement. The ATR-ATRIP structure illuminates regulatory regions such as the PRD and Bridge domains that could be potentially targeted by more efficient ATR inhibitor design.
The specific ATR inhibitors may be developed to lock the ATR kinase into the inactive state. Therefore, the work provides a molecular blueprint for the development of novel ATR inhibitors as potential cancer therapeutic agents.
(USTC News Center)
