Detailed Structure Illuminates Brain-Enhancing Drug’s Action

Source: Howard Hughes Medical Institute

Summary: Researchers have shown that the drug, nicknamed ISRIB, completely eliminates learning and memory deficits in mice with concussions.

Cells in our bodies respond to stressors such as viral infections, starvation, and injury in the same way: by restricting the production of new proteins. This “cellular stress response” helps keep cells alive by buying them time to recover. But in many cases, this response can be maladaptiveTraumatic brain injury persistently turns on the cellular stress response and the resulting drop in protein production may slow critical cognitive processes. Learning and storing memories, for example, requires brain cells to produce proteins that help create long-lasting connections in the brain. Researchers from the Howard Hughes Medical Institute have shown that the drug, nicknamed ISRIB, completely eliminates learning and memory deficits in mice with concussions. The detailed picture of a brain-boosting experimental drug could one day help researchers tailor it for use in human clinical trials. The study findings were published in the journal Science.


Using cryo-electron microscopy, researchers have revealed atomic-level details of the interactions between ISRIB, a brain-boosting experimental drug, (propeller-shaped molecule, center), and its target protein, eIF2B. Credit: J. Tsai et al./Science 2018

This study will give scientists a clearer view of how ISRIB works by pinning together parts of a protein involved in cellular stress. Tracking how ISRIB interacts with its protein target could potentially help researchers modify the drug to treat traumatic brain injury and neurodegeneration in humans. A closer look revealed that ISRIB was 1,000 times more potent than many of the other molecular options. So even the tiny amount of ISRIB that can enter cells was enough to provoke a response. The researchers saw that the propeller-shaped ISRIB sits deep inside eIF2B and acts as a molecular staple to pin two identical subcomplexes together. Stressed cells dosed with the drug began synthesizing proteins again and remarkably, ISRIB enhanced learning and memory in mice.

Investigator Peter Walter said, “We can see with almost atomic resolution where the drug binds to the protein”, “The current idea is that ISRIB holding the eIF2B complex together may be enough to stabilize the protein and increase its activity.”

More Information: Alisa F. Zyryanova et al, “Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B”, Science (2018). … 1126/science.aar5129

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