8CUG

Synthetic epi-Novo29 (2R,3S), synchrotron structure

Summary for 8CUG

• Entry DOI: 10.2210/pdb8cug/pdb
• Descriptor: Synthetic epi-Novo29 (2R,3S), ACETATE ION (3 entities in total)
• Functional Keywords: macrocyclic peptide, antibiotic
• Biological source: Eleftheria
• Total number of polymer chains: 2
• Total formula weight: 1901.23

Authors

Kreutzer, A.G.,Li, X.,Krumberger, M.,Nowick, J.S. (deposition date: 2022-05-17, release date: 2023-01-11, Last modification date: 2023-11-15)

Primary citation

Krumberger, M.,Li, X.,Kreutzer, A.G.,Peoples, A.J.,Nitti, A.G.,Cunningham, A.M.,Jones, C.R.,Achorn, C.,Ling, L.L.,Hughes, D.E.,Nowick, J.S.
Synthesis and Stereochemical Determination of the Peptide Antibiotic Novo29.
J.Org.Chem., 88:2214-2220, 2023

PubMed Abstract: This paper describes the synthesis and stereochemical determination of Novo29 (clovibactin), a new peptide antibiotic that is related to teixobactin and is active against Gram-positive bacteria. Novo29 is an eight-residue depsipeptide that contains the noncanonical amino acid hydroxyasparagine of hitherto undetermined stereochemistry in a macrolactone ring. The amino acid building blocks Fmoc-(2,3)-hydroxyasparagine-OH and Fmoc-(2,3)-hydroxyasparagine-OH were synthesized from (,)- and (,)-diethyl tartrate. Novo29 and -Novo29 were then prepared by solid-phase peptide synthesis using these building blocks. Correlation with an authentic sample of Novo29 through H NMR spectroscopy, LC-MS, and antibiotic activity established that Novo29 contains (2,3)-hydroxyasparagine. X-ray crystallography reveals that -Novo29 adopts an amphiphilic conformation, with a hydrophobic surface and a hydrophilic surface. Four sets of -Novo29 molecules pack in the crystal lattice to form a hydrophobic core. The macrolactone ring adopts a conformation in which the main-chain amide NH groups converge to create a cavity, which binds ordered water and acetate anion. The amphiphilic conformation of -Novo29 is reminiscent of the amphiphilic conformation adopted by the related antibiotic teixobactin and its derivatives, which contains a hydrophobic surface that interacts with the lipids of the bacterial cell membrane and a hydrophilic surface that interacts with the aqueous environment. Molecular modeling suggests that Novo29 can adopt an amphiphilic conformation similar to teixobactin, suggesting that Novo29 may interact with bacteria in a similar fashion to teixobactin.

PubMed: 36655882
DOI: 10.1021/acs.joc.2c02648

Experimental method

X-RAY DIFFRACTION (1.131 Å)