The new method enables researchers to quickly find small molecules that bind to hundreds of thousands of proteins in their native cellular environment.
These molecules, called ligands, can be developed into important tools for studying how proteins work in cells, which may lead to the development of new drugs.
The method can be used to discover ligand molecules that disrupt a biological process and quickly identify the proteins to which they bind.
It involves developing of a set of small but structurally varied candidate ligand molecules known as fragments.
Each fragment is modified with a special chemical compound, so that when it binds with moderate affinity to a protein partner, brief exposure to UV light makes them stick permanently.
A further modification provides a molecular handle for scientists to grab, so they can isolate the ligand-protein pairs for analysis.
To begin, the team assembled a small library of candidate ligands whose structural features include many found in existing drugs.
By applying 11 of them to human cells, the researchers identified more than 2,000 distinct proteins bound to one or more of the ligands.
These ligand-bound proteins include many categories that had previously been considered un-ligandable and therefore un-targetable with drugs — such as transcription factors.
The research team then tested the ligands to find any that could promote the maturation of fat cells—a process that in principle can alleviate the insulin resistance that leads to type 2 diabetes.
With this new discovery method, the researchers found a ligand that promotes adipocyte maturation. They also discovered its binding partner, PGRMC2, a protein about which little was known.
“We found a new ‘druggable’ pathway, and we also seem to have uncovered some new biology—despite the fact that adipocyte maturation and other diabetes-related pathways have been studied a lot already,” said Christopher G. Parker, a research associate in the laboratory of TSRI Professor Benjamin F. Cravatt, Chairman of the Department of Chemical Biology.
“With this method, we look forward to exploring much more thoroughly the druggability of human proteins and accelerating investigations of protein biology,” Cravatt added.