Poster Presentation 13th Australian Peptide Conference 2019

In-cell structure determination of an antimicrobial peptide by DNP solid-state NMR (#222)

shiying zhu 1 , Frances Separovic 1 , Marc-Antoine Sani 1
  1. University of Melbourne, Melbourne, Victoria, Australia

 As bacteria develop increasing resistance to antibiotics, antimicrobial peptides (AMPs) are possible alternatives to conventional treatments. Maculatin 1.1 (Mac1) is a cationic AMP isolated from the skin glands of the Australian tree frog Litoria genimaculata with low micromolar activity against Gram-positive bacteria.1 The molecular mechanism of Mac1 has been well studied in vitro but there is a scarcity of info in vivo studies. 2-3 Solid-state nuclear magnetic resonance (ss-NMR) is a valuable tool to investigate peptide-membrane interactions but its application in vivo is restricted due to its inherent insensitivity and short lifespan of bacteria. However, Dynamic Nuclear Polarization (DNP) NMR enables in-cell experiments due to enhanced sensitivity and longer cell survival at the low temperatures used. Free electrons or spin labels together with isotope enriched peptides are needed for DNP-NMR structural studies. Hence, we designed mono- and bi-radical nitroxide (TOAC) spin-labelled peptides, TOAC-MacW and TOAC-TOAC-MacW, as a vector to locate radical sources within cell membranes. In-cell NMR results showed that mono- and bi-TOAC radicals induced more localized 13C signal enhancement compared to the more hydrophilic radical AMUPol.4 Circular dichroism and solution NMR spectroscopy revealed that the spin-labelled peptides adopt a helical conformation in lipid environments. We then used an E. coli-based expression method to achieve isotope labelling of Mac1 with C-amidation to facilitate site-specific interrogation of structure and intermolecular contacts. A protocol for expression and purification of milligram quantities of amidated and uniformly 15N labelled Mac1 will be presented.

 

 

  1. [1] B.C.S. Chia, J.A. Carver, T.D. Mulhern, J.H. Bowie, Eur. J. Biochem. 267, 1894-1908 (2000). [2] M.-A. Sani, F. Separovic, Acc. Chem. Res. 49, 1130-1138 (2016). [3] M.-A. Sani, T. C. Whitwell, F. Separovic, Biochim. Biophys. Acta 1818, 205-211 (2012). [4] M.-A. Sani, S. Zhu, V. Hofferek, F. Separovic. Nitroxide spin labelled peptides for DNP-NMR in-cell studies. FASEB J. (under revision)