Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-kappaB. (https://pubmed.ncbi.nlm.nih.gov/38670073/)

These scientists wanted to understand how a specific molecule called NF-kappaB is involved in causing diseases. They focused on a signal called lipopolysaccharides (LPSs) that can activate NF-kappaB in our cells. They discovered that a receptor called Toll-like receptor 4 (TLR4) needs a complex called OST-A to work properly and be located on the cell surface.

To further study this, they used a tool compound called NGI-1 to block the OST complexes in cells. They then looked for cells that were resistant to NGI-1 by editing their DNA using a tool called CRISPR base-editor. This helped them identify specific changes in a protein called STT3A that made cells resistant to NGI-1.

By studying the structure of these proteins using a technique called cryoelectron microscopy, they found that NGI-1 binds to a specific part of STT3A and stops it from working properly. This helps us understand how NGI-1 can block the function of STT3A and provides a starting point for developing new drugs that can target this protein.

In simple terms, these scientists found a way to block a protein that is important for causing diseases, which could help in developing new treatments in the future.

Lampson BL., Ramiotarez AS., Baro M., He L., Hegde M., Koduri V., Pfaff JL., Hanna RE., Kowal J., Shirole NH., He Y., Doench JG., Contessa JN., Locher KP., Kaelin WG Jr. Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-kappaB. Cell. 2024 Apr 25;187(9):2209-2223.e16. doi: 10.1016/j.cell.2024.03.022.