Nonribosomal Peptide Synthetases
One target of our research is a family of enzymes called nonribosomal peptide synthetases (NRPSs). The NRPS enzymes catalyze the formation of peptide natural products. These peptides are important as some exhibit antibiotic or anti-cancer activities; other NRPS clusters are responsible for the synthesis of peptide siderophores, compounds that bind to iron with high affinity. The NRPSs are modular enzymes that, like fatty acid synthases and polyketide synthases, contain multiple catalytic enzyme activities joined in a single multi-domain protein that can be thousands of residues in length. Each module is responsible for the incorporation of a single residue of the final peptide.
Structural Biology of NRPS enzymes
The structures of individual NRPS domains have been determined to provide insights into the catalytic activities. Additionally, structures of multidomain NRPS enzymes have been determined that identify the structural foundation for activity by these assembly line proteins. A large conformational change within the adenylation domain, for example, results in a domain rearrangement that allows the adenylation domain to adopt a conformation that is used to bind to the carrier protein domain for loading. After loading, the adenylation domain reverts to a conformation that delivers the loaded carrier protein domain directly to the upstream condensation domain.