The lantibiotic nukacin ISK-1 exists in an equilibrium between active and inactive lipid-II binding states

Daisuke Fujinami,Takeshi Zendo,Sabrina Momin,Mohammad R Islam,Abdullah-Al -Mahin,Kenji Sonomoto,Khaled M Elsayed,Urmi Roy,Daisuke Kohda,Jun-Ichi Nagao

doi:10.1038/s42003-018-0150-3

Abstract

The lantibiotic nukacin ISK-1 exerts antimicrobial activity through binding to lipid II. Here, we perform NMR analyses of the structure of nukacin ISK-1 and the interaction with lipid II. Unexpectedly, nukacin ISK-1 exists in two structural states in aqueous solution, with an interconversion rate on a time scale of seconds. The two structures differ in the relative orientations of the two lanthionine rings, ring A and ring C. Chemical shift perturbation induced by the titration of lipid II reveals that only one state was capable of binding to lipid II. On the molecular surface of the active state, a multiple hydrogen-bonding site formed by amino acid residues in the ring A region is adjacent to a hydrophobic surface formed by residues in the ring C region, and we propose that these sites interact with the pyrophosphate moiety and the isoprene chain of the lipid II molecule, respectively.

Highlights

The lantibiotic nukacin ISK-1 exerts antimicrobial activity through binding to lipid II
We found that the pH change from 6.0 to 3.5 and the addition of a sub-stoichiometric amount of dodecylphosphocholine (DPC, 0.05 micelle/nukacin ISK-1) were effective to increase the number of NOEs at 326 K
We propose that the dynamic equilibrium between multiple states would be a characteristic property of lantibiotics belonging to the lacticin 481 group

Summary

Introduction

The lantibiotic nukacin ISK-1 exerts antimicrobial activity through binding to lipid II. On the molecular surface of the active state, a multiple hydrogen-bonding site formed by amino acid residues in the ring A region is adjacent to a hydrophobic surface formed by residues in the ring C region, and we propose that these sites interact with the pyrophosphate moiety and the isoprene chain of the lipid II molecule, respectively. These authors contributed : Daisuke Fujinami, Abdullah-Al-Mahin. Antimicrobial peptides possessing lanthionine or methyllanthionine residues are referred to as lantibiotics (Fig. 1a). The resultant monosulfide bridge structures, derived from a serine and cysteine pair and a threonine and cysteine pair, are referred to as lanthionine and methyllanthionine, respectively (Fig. 1a). The two major groups are referred to as lacticin 481 and mersacidin, of which members share a conserved lipid II binding motif[8] (Fig. 1c)

Methods

Results

Conclusion