A path toward drug synthesis in cells

A Yale-led research team has described the structure of pyrrolysyl-tRNA synthetase (PylRS), a protein that synthetic biologists rely upon to add new letters to the genetic code.

In the past, most biology textbooks have described 20 amino acids—the building blocks of all proteins— and 20 tRNA synthetases, responsible for matching the amino acids with the correct genetic molecules. Recently, however, researchers have uncovered additional rare amino acids, including the so-called “22nd amino acid” pyrrolysine, found in bacteria and single-celled organisms.

To help advance efforts to integrate pyrrolysine into the genomes of other types of cells, Dieter Söll, Ph.D., Sterling Professor of Molecular Biophysics and Biochemistry, and professor of chemistry, and colleagues determined the three-dimensional structure of PylRS—the tRNA synthetase required for pyrrolysine.

As published October 16 in Nature Chemical Biology, Söll’s team not only described the structure of a unique section of PylRS, but also evolved new variants of the protein using a standard lab setup that is both simpler and faster than prior techniques that need specialized equipment. Söll foresees “the exciting prospect of synthesizing new drugs inside living cells.”