There has been growing interest in developing drugs that bind two or more proteins to “glue” them together.
Tacrolimus (aka FK506) is a famous example. Tacrolimus is an immune-suppressant that is often used to prevent patients from rejecting organ transplants. It works by inhibiting an enzyme called calcineurin by gluing it to another protein called FKBP. Interestingly, FK506 was not designed to do this. It is a natural product that was isolated from a soil sample. Its surprising mechanism was discovered later, and led to an new field of trying to understand and design new molecular glues.
Now we’ve discovered that another well-known natural product has a surprising mechanism.
A natural product called YM is known to inhibit one type of G proteins without impacting others. This specificity is important because it means that YM, or related compounds, could be used to treat cancer without having nasty side effects.
In a new preprint, we now show that YM is an allosteric glue. Like other glues, YM brings two proteins together. However, it turns out to barely touch one of them. Instead it works by a process called allostery, binding to one part of a protein (called Gα) and altering the structure of a distant part of that protein. YM’s long-range (or allosteric) effect on a distant part of the Gα protein it binds causes that protein to stick more tightly to a second protein (called Gβ) without YM having to directly touch that second protein!
