September 11, 2024

Scripps Research scientists expand the genetic alphabet to create new proteins The novel method uses sets of four RNA nucleotides rather than the natural three to encode new, synthetic building blocks into proteins.

September 11, 2024

LA JOLLA, CA It's a dogma taught in every introductory biology class: Proteins are composed of combinations of 20 different amino acids, arranged into diverse sequences like words. But researchers trying to engineer biologic molecules with new functions have long felt limited by those 20 basic building blocks and strived to develop ways of putting new building blocks called non-canonical amino acids into their proteins.

Now, scientists at Scripps Research have designed a new paradigm for easily adding non-canonical amino acids to proteins. Their approach, described in Nature Biotechnology on September 11, 2024, revolves around using four RNA nucleotides rather than the typical three to encode each new amino acid.

Our goal is to develop proteins with tailored functions for applications in fields spanning bioengineering to drug discovery, says senior author Ahmed Badran, PhD, an assistant professor of chemistry at Scripps Research. Being able to incorporate non-canonical amino acids into proteins with this new method gets us closer to that goal.

For a cell to produce any given protein, it must translate a strand of RNA into a string of amino acids. Every three nucleotides of RNA, called a codon, correspond to one amino acid. But many amino acids have more than one possible codon; for instance, RNA reading the sequences UAU and UAC both correspond to the amino acid tyrosine. It's the job of small molecules called transfer RNAs (tRNAs) to link each amino acid to its corresponding codons.

Recently, researchers aiming to add completely new amino acids to a protein have created strategies to reassign a codon. For instance, the UAU codon could be linked to a new amino acid by changing the tRNA for UAU; this would result in UAU being read by the cell as corresponding to a building block other than tyrosine. But at the same time, every instance of UAU in the cell's genome would need to become UAC, in order to prevent the new amino acid from being integrated into thousands of other proteins where it doesn't belong.

Ahmed Badran, PhD. Credit: Scripps research

LINK:	https://www.scripps.edu/news-and-events/press-room/2024/2024911-badran...
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