Proteins are very large, complicated molecules with highly involved synthesis processes, so building them is a complex task. The molecular machinery involved in carrying out this process is incredible — ribosomes, mRNA, tRNA, and a multitude of other proteins and chemicals come together and work in precise order, every time a new protein is produced in your body.

Protein synthesis visualized. Source: Said Sannuga, Cellscape UK

As its name suggests, this February’s MotM plays a role in initiating this complicated synthesis. eIF4E is part of a key group of proteins called initiation factors. It is responsible for identifying messenger RNAs ready for translation, and then directing the other initiation factors onto the mRNA. It does this by binding to a methylated guanine nucleotide cap on the end of mRNA chains. This cap is a characteristic feature of mRNAs in eukaryotes (like you and me). eIF4E then brings in the rest of the 4F initiation machinery, which can be seen in complex here.

A closer look at the cap-binding region on eIF4E—highlighted is the methylated guanine nucleotide

For readers with less background knowledge, here’s a video on the initiation process of eukaryotic protein translation. It provides helpful context about the process and the roles of all the different initiation factors.

Given its critical role in protein synthesis, the function of eIF4E is essential to cell growth. Normally, cells have built-in limits that control the speed of cell growth. Cancer cells find ways around these limits in order to grow rapidly. One way that cancer cells do this is by developing hyperactive eIF4E proteins, enabling them to grow quickly.

Checking out the structure of eIF4E-inhibitor complex

This makes eIF4E an interesting target for anti-cancer research to medical scientists. Recent studies have shown that eIF4E inhibitors can help fight the growth of tumors. By using X-ray crystallography to examine protein-inhibitor complex, researchers at Harvard Medical School showed how this inhibition works. We took this structure into Nanome to take a closer look.

The small molecule drug (4EGI-1[E]) blocks the assembly of the other initiation factors onto eIF4E. When these parts can’t connect to each other, protein synthesis is essentially halted, because without the initiation factor assembly, there’s nothing to direct the ribosome (protein making machine) onto the mRNA (protein code). It does this by inducing structural changes to the protein chains in eIF4E when it binds, which changes the shape of the site where eIF4E binds to the next initiation factor in the process.

Showing the drug binding site vs the protein binding site

The drug-bound version of of eIF4E (multicolored) doesn’t fit well with eIF4G (red), impacting the protein synthesis process

It’s pretty cool that this drug molecule can disrupt a tumor’s growth by changing the shape of just one protein. We think that getting a hands-on experience of the molecules responsible transforms this from abstract and interesting to something tangible and amazing. We hope this post inspires your curiosity in the way things are working down at the molecular level, and that you feel empowered to get out there and explore these structures on your own. If you want to check them out in VR, Nanome can be downloaded for free on Oculus, SteamVR, and Viveport.