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Updated: Jun 17, 2026

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
Published on: September 28, 2022
Structural Insights into the Cyclic Peptide Antibiotic Thiostrepton via NMR Spectroscopy
Bijay Laxmi Pradhan1,2, Prince Sen3, Poulomi Ghosh4
1Department of Physics, Institute of Science, Banaras Hindu University, Varanasi, Uttar-Pradesh 221005, India.
None:
A complex cyclic polypeptide antibiotic, thiostrepton, is made by two large macrocyclic rings: a 26-membered ring associated with a thiazoline moiety and a 27-membered ring accompanied by a quinaldic acid unit, a dehydropiperidine ring, and a flexible bis-dehydroalanine tail. The site-specific local structure and nuclear-spin dynamics of this polypeptide antibiotic is determined by using 2D solution NMR (1H-13C HSQC, 1H-13C HMBC, 1H-1H COSY, 1H-1H TOCSY, and 1H-1H NOESY) and solid-state NMR methods (13C CP-MAS 2D PASS, 1H-13C HETCOR, and site-specific 13C spin-lattice relaxation measurements). The combined 1H-13C HETCOR and 1H-1H NOESY data demonstrate that the quinaldic acid residue is positioned in close spatial proximity to multiple structural elements, including the thiazoline and piperidine rings, isoleucine-valine chain, butyrine, thiostreptin residue, dehydroalanine units, threonine, and thiazole. These interactions generate a compact hydrophobic core that stabilizes the conformation of the bis-dehydroalanine tail. The flexible side chains of both macrocyclic rings, together with the tail region, accommodate themselves within the interface of ribosomal protein L11 and the 23S rRNA, thereby perturbing the 70S ribosomal subunit. The dynamics of these flexible segments are quantified by employing NMR relaxometry. Therefore, although functional activity is not examined directly, the integrated solution- and solid-state NMR results deliver site-specific structural information and local nuclear spin dynamics at individual carbon sites of this cyclic polypeptide antibiotic. These characteristics are associated with the functional state of thiostrepton and offer a foundation for the rational design of next-generation polypeptide antibiotics.
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