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PDBsum entry 1mqy
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References listed in PDB file
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Key reference
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Title
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Nmr study of mersacidin and lipid ii interaction in dodecylphosphocholine micelles. Conformational changes are a key to antimicrobial activity.
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Authors
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S.T.Hsu,
E.Breukink,
G.Bierbaum,
H.G.Sahl,
B.De kruijff,
R.Kaptein,
N.A.Van nuland,
A.M.Bonvin.
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Ref.
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J Biol Chem, 2003,
278,
13110-13117.
[DOI no: ]
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PubMed id
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Abstract
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Mersacidin belongs to the type B lantibiotics (lanthionine-containing
antibiotics) that contain post-translationally modified amino acids and cyclic
ring structures. It targets the cell wall precursor lipid II and thereby
inhibits cell wall synthesis. In light of the emerging antibiotics resistance
problem, the understanding of the antibacterial activity on a structural basis
provides a key to circumvent this issue. Here we present solution NMR studies of
mersacidin-lipid II interaction in dodecylphosphocholine (DPC) micelles.
Distinct solution structures of mersacidin were determined in three different
states: in water/methanol solution and in DPC micelles with and without lipid
II. The structures in various sample conditions reveal remarkable conformational
changes in which the junction between Ala-12 and Abu-13 (where Abu is
aminobutyric acid) effectively serves as the hinge for the opening and closure
of the ring structures. The DPC micelle-bound form resembles the previously
determined NMR and x-ray crystal structures of mersacidin in pure methanol but
substantially deviates from the other two states in our current report. The
structural changes delineate the large chemical shift perturbations observed
during the course of a two-step (15)N-(1)H heteronuclear single quantum
coherence titration. They also modulate the surface charge distribution of
mersacidin suggesting that electrostatics play a central role in the
mersacidin-lipid II interaction. The observed conformational adaptability of
mersacidin might be a general feature of lipid II-interacting
antibiotics/peptides.
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Figure 1.
Fig. 1. Primary structures of mersacidin (A) and lipid II
(B). A, post-translationally modified amino acids are
highlighted in gray, and their chemical structures are depicted
below. B, GlcNAc, N-acetylglucosamine; MurNAc, N-acetylmuramic
acid.
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Figure 8.
Fig. 8. A, representative structures (closest to average)
of each structure ensemble. The Glu-17 side chain is shown in
red. The hinge residue Abu-13 is shown in green. The structures
were fitted on backbone heavy atoms of residues 13-20 (colored
blue). The remainder of the structure is shown in gray. B,
surface electrostatic potential of mersacidin in different
sample conditions calculated with MOLMOL (40). Positive and
negative potentials are colored blue and red, respectively. The
structures are in the same orientation as in A. C, 90°
rotation along the x axis of the above structures. The charge
distributions reveal the increase of charge accessibility after
the addition of lipid II in the hydrophobic DPC micelle
solution. The structure of mersacidin in DPC micelles resembles
the x-ray structure that was solved in pure methanol.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
13110-13117)
copyright 2003.
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