6B34

NMR ensemble of Tyrocidine A analogue AC3.27

Summary for 6B34

• Entry DOI: 10.2210/pdb6b34/pdb
• NMR Information: BMRB: 30346
• Related PRD ID: PRD_002289
• Descriptor: Tyrocidine A analogue D-PHE-BE2-PHE-D-PHE-ASN-GLN-TYR-VAL-ORN-LEU (1 entity in total)
• Functional Keywords: tyrocidine a antimicrobial peptide amp cyclic peptide 2-aminobenzoic acid 2-abz anthranilic acid, antimicrobial protein
• Biological source: Brevibacillus brevis
• Total number of polymer chains: 1
• Total formula weight: 1310.50

Authors

Cameron, A.J.,Ewdards, P.J.B.,Harjes, E.,Sarojini, V. (deposition date: 2017-09-20, release date: 2017-12-06, Last modification date: 2023-11-15)

Primary citation

Cameron, A.J.,Edwards, P.J.B.,Harjes, E.,Sarojini, V.
Tyrocidine A Analogues Bearing the Planar d-Phe-2-Abz Turn Motif: How Conformation Impacts Bioactivity.
J. Med. Chem., 60:9565-9574, 2017

PubMed Abstract: The d-Phe-Pro β-turn of the cyclic β-hairpin antimicrobial decapeptide tyrocidine A, (Tyrc A) was substituted with the d-Phe-2-aminobenzoic acid (2-Abz) motif in a synthetic analogue (1). The NMR structure of 1 demonstrated that compound 1 retained the β-hairpin structure of Tyrc A with additional planarity, resulting in approximately 30-fold reduced hemolysis than Tyrc A. Although antibacterial activity was partially compromised, a single Gln to Lys substitution (2) restored activity equivalent to Tyrc A against S. aureus, enhanced activity against two Gram negative strains and maintained the reduced hemeloysis of 1. Analysis by transmission electron microscopy (TEM) suggested a membrane lytic mechanism of action for these peptides. Compound 2 also exhibits nanomolar antifungal activity in synergy with amphotericin B. The d-Phe-2-Abz turn may serve as a tool for the synthesis of structurally predictable β-hairpin libraries. Unlike traditional β-turn motifs such as d-Pro-Gly, both the 2-Abz and d-Phe rings may be further functionalized.

PubMed: 29140694
DOI: 10.1021/acs.jmedchem.7b00953

Experimental method

SOLUTION NMR