Biochemists Present First 3D Crystal Structure of a Nonribosomal Peptide Synthetase

NRPSs are very large proteins that produce small peptide molecules with wide-ranging biological activities. Each nonribosomal peptide synthetase can synthesize only one type of peptide. Nonribosomal peptides often have cyclic and/or branched structures, can contain non-proteinogenic amino acids including D-amino acids, carry modifications like N-methyl and N-formyl groups, or are glycosylated, acylated, halogenated, or hydroxylated. Cyclization of amino acids against the peptide "backbone" is often performed, resulting in oxazolines and thiazolines; these can be further oxidized or reduced. On occasion, dehydration is performed on serines, resulting in dehydroalanine. This is just a sampling of the various manipulations and variations that nonribosomal peptides can perform.

In the January 14, 2016, issue of the journal Nature, investigators at McGill University (Montreal, QC, Canada) presented a series of three-dimensional X-ray crystal structures of the initiation module of the antibiotic-producing NRPS, linear gramicidin synthetase. This module included the specialized tailoring formylation domain, and states were captured that represented every major step of the assembly-line synthesis in the initiation module.

The investigators reported that the transitions between conformations were large in scale, with both the peptidyl carrier protein domain and the adenylation subdomain undergoing huge movements to transport substrate between distal active sites. The structures highlighted the great versatility of NRPSs, as small domains repurposed and recycled their limited interfaces to interact with their various binding partners.

"This is the most complete view we have ever had of these enzymes in action," said senior author Dr. Martin Schmeing, professor of biochemistry at McGill University. "Even though megaenzymes are the second-biggest proteins known to man, they are still very small molecules and they are very mobile, so it is difficult to see them at work."

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