6NM2

NMR Structure of WW291

Summary for 6NM2

• Entry DOI: 10.2210/pdb6nm2/pdb
• NMR Information: BMRB: 30557
• Descriptor: WW291 peptide (1 entity in total)
• Functional Keywords: antimicrobial protein
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 1273.55

Authors

Wang, G.,Zarena, D. (deposition date: 2019-01-10, release date: 2020-07-15, Last modification date: 2024-10-30)

Primary citation

Zarena, D.,Mishra, B.,Lushnikova, T.,Wang, F.,Wang, G.
The pi Configuration of the WWW Motif of a Short Trp-Rich Peptide Is Critical for Targeting Bacterial Membranes, Disrupting Preformed Biofilms, and Killing Methicillin-Resistant Staphylococcus aureus.
Biochemistry, 56:4039-4043, 2017

PubMed Abstract: Tryptophan-rich peptides, being short and suitable for large-scale chemical synthesis, are attractive candidates for developing a new generation of antimicrobials to combat antibiotic-resistant bacteria (superbugs). Although there are numerous pictures of the membrane-bound structure of a single tryptophan (W), how multiple Trp amino acids assemble themselves and interact with bacterial membranes is poorly understood. This communication presents the three-dimensional structure of an eight-residue Trp-rich peptide (WWWLRKIW-NH with 50% W) determined by the improved two-dimensional nuclear magnetic resonance method, which includes the measurements of C and N chemical shifts at natural abundance. This peptide forms the shortest two-turn helix with a distinct amphipathic feature. A unique structural arrangement is identified for the Trp triplet, WWW, that forms a π configuration with W2 as the horizontal bar and W1/W3 forming the two legs. An arginine scan reveals that the WWW motif is essential for killing methicillin-resistant Staphylococcus aureus USA300 and disrupting preformed bacterial biofilms. This unique π configuration for the WWW motif is stabilized by aromatic-aromatic interactions as evidenced by ring current shifts as well as nuclear Overhauser effects. Because the WWW motif is maintained, a change of I7 to R led to a potent antimicrobial and antibiofilm peptide with 4-fold improvement in cell selectivity. Collectively, this study elucidated the structural basis of antibiofilm activity of the peptide, identified a better peptide candidate via structure-activity relationship studies, and laid the foundation for engineering future antibiotics based on the WWW motif.

PubMed: 28731688
DOI: 10.1021/acs.biochem.7b00456

Experimental method

SOLUTION NMR