In Project 10490, the Chodera lab is studying a small protein called KRAS, which forms a key link in growth signaling and cancer. This gene is something like a molecular switch with a timer. When it is bound to a molecule called GDP, it is off, and does not signal that the cell should grow. However, other proteins can cause it to swap its GDP for a GTP, turning KRAS on. In the on state, it signals that the cell should grow and divide. Normally, after some time, KRAS, with the aid of some partners, will chemically convert its GTP to GDP and return to its inactive state.
In many cancers, this protein becomes mutated, and cannot return to its off state. The result? The cells continue to divide without limit. What’s worse, cancers with this protein mutated tend to have much poorer prognoses. As a result, scientists have been trying to target this protein for decades. So what’s the problem?
As you can see in the picture (3GFT in the PDB, for the curious), the only “reasonable’ site for a small-molecule drug to bind is where the GDP or GTP binds, represented here as sticks. However, the affinity that KRAS has for the GDP/GTP is so high that it is considered virtually impossible to outcompete. All is not lost though— proteins move, and in the course of their fluctuations, occasionally expose sites where a molecule could bind. These are invisible on most experimental techniques (like the one used for the previous picture, x-ray crystallography), but may become visible in long molecular simulations. These so-called cryptic binding sites (which have been discovered for other therapeutically interesting proteins like Beta-lactamase using Folding@Home) offer a potential to “drug the undruggable,” and create novel therapeutics for previously intractable diseases.