One of the Bowman lab’s major foci is on finding and targeting cryptic pockets.
Cryptic pockets are absent in experimentally derived structures of what a protein typically looks like but open up due to protein dynamics.
The ability to find and target cryptic pockets would be of great therapeutic value. For example, many proteins that are implicated in disease are currently considered undruggable because there aren’t obvious pockets in known structures of the protein where a drug could bind. Finding cryptic pockets in such proteins could provide a means to target them, expanding the set of proteins thought to be druggable.
One outstanding question is why cryptic pockets exist? Are they just happenstance? Or do they have a role in protein function?
This question is both fascinating and of enormous practical importance. For example, if a cryptic pocket in a viral protein is just happenstance, then it may be easy for the virus to evolve resistance to a drug that targets that pocket. The virus could mutate so the pocket no longer exists, the drug wouldn’t work anymore, and the virus would continue infecting people. If, on the other hand, the cryptic pocket is important for function, then drug resistance might be much harder to evolve. Any mutation that closed the cryptic pocket would also make it harder for the virus to survive.
In a new preprint, Mallimadugula et al. show that a cryptic pocket that we discovered in an Ebola protein, called VP35, has a function! This protein binds to two different parts of the virus’ genome to block our immune systems from recognizing the presence of an infection and mounting a defense until it’s too late. It was previously thought that the same structure of VP35 bound to both parts of RNA. However, now we know that the structure of VP35 with the open cryptic pocket is far better at binding one part of RNA than the previously known closed structure. The immediate implication is that drugging the cryptic pocket in VP35 would be a reasonable therapeutic strategy for preventing Ebola.