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PDBsum entry 4m6e
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References listed in PDB file
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Key reference
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Title
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The high resolution structure of tyrocidine a reveals an amphipathic dimer.
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Authors
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P.J.Loll,
E.C.Upton,
V.Nahoum,
N.J.Economou,
S.Cocklin.
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Ref.
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Biochim Biophys Acta, 2014,
1838,
1199-1207.
[DOI no: ]
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PubMed id
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Abstract
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Tyrocidine A, one of the first antibiotics ever to be discovered, is a cyclic
decapeptide that binds to membranes of target bacteria, disrupting their
integrity. It is active against a broad spectrum of Gram-positive organisms, and
has recently engendered interest as a potential scaffold for the development of
new drugs to combat antibiotic-resistant pathogens. We present here the X-ray
crystal structure of tyrocidine A at a resolution of 0.95Å. The structure
reveals that tyrocidine forms an intimate and highly amphipathic homodimer made
up of four beta strands that associate into a single, highly curved antiparallel
beta sheet. We used surface plasmon resonance and potassium efflux assays to
demonstrate that tyrocidine binds tightly to mimetics of bacterial membranes
with an apparent dissociation constant (KD) of 10μM, and efficiently
permeabilizes bacterial cells at concentrations equal to and below the KD. Using
variant forms of tyrocidine in which the fluorescent probe p-cyano-phenylalanine
had been inserted on either the polar or apolar face of the molecule, we
performed fluorescence quenching experiments, using both water-soluble and
membrane-embedded quenchers. The quenching results, together with the structure,
strongly support a membrane association model in which the convex, apolar face
of tyrocidine's beta sheet is oriented toward the membrane interior, while the
concave, polar face is presented to the aqueous phase.
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Headers
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