8CWX
NMR structure of a Stapled Lanthipeptide Natural Product
Summary for 8CWX
| Entry DOI | 10.2210/pdb8cwx/pdb |
| NMR Information | BMRB: 31024 |
| Descriptor | Lanthipeptide Natural Product mSmoAc (1 entity in total) |
| Functional Keywords | a-helix, biosynthesis, stapled peptide, natural product, biosynthetic protein |
| Biological source | Streptomyces morookaense |
| Total number of polymer chains | 1 |
| Total formula weight | 2783.14 |
| Authors | Pei, Z.,Zhu, L.,Nair, S.K. (deposition date: 2022-05-19, release date: 2022-10-12, Last modification date: 2024-07-10) |
| Primary citation | Pei, Z.F.,Zhu, L.,Sarksian, R.,van der Donk, W.A.,Nair, S.K. Class V Lanthipeptide Cyclase Directs the Biosynthesis of a Stapled Peptide Natural Product. J.Am.Chem.Soc., 144:17549-17557, 2022 Cited by PubMed Abstract: Lanthipeptides are a class of cyclic peptides characterized by the presence of one or more lanthionine (Lan) or methyllanthionine (MeLan) thioether rings. These cross-links are produced by α,β-unsaturation of Ser or Thr residues in peptide substrates by dehydration, followed by a Michael-type conjugate addition of Cys residues onto the dehydroamino acids. Lanthipeptides may be broadly classified into at least five different classes, and the biosynthesis of classes I-IV lanthipeptides requires catalysis by LanC cyclases that control both the site-specificity and the stereochemistry of the conjugate addition. In contrast, there are no current examples of LanCs that occur in class V biosynthetic clusters, despite the presence of lanthionine rings in these compounds. In this work, bioinformatics-guided co-occurrence analysis identifies more than 240 putative class V lanthipeptide clusters that contain a LanC cyclase. Reconstitution studies demonstrate that the cyclase-catalyzed product is notably distinct from the product formed spontaneously. Stereochemical analysis shows that the cyclase diverts the final product to a configuration that is distinct from one that is energetically favored. Structural characterization of the final product by multi-dimensional NMR spectroscopy reveals that it forms a helical stapled peptide. Mutational analysis identified a plausible order for cyclization and suggests that enzymatic rerouting to the final structure is largely directed by the construction of the first lanthionine ring. These studies show that lanthipeptide cyclases are needed for the biosynthesis of some constrained peptides, the formations of which would otherwise be energetically unfavored. PubMed: 36107785DOI: 10.1021/jacs.2c06808 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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