Three-dimensional solution structure of bottromycin A2: a potent antibiotic active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci.
ABSTRACT The three-dimensional (3D) structure of bottromycin A(2), a natural anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-vancomycin-resistant Enterococci (VRE) agent consisting of seven amino acids, has been investigated through NMR spectroscopy. On the basis of 57 experimental constraints, a total of 34 converged structures were obtained. The average pairwise atomic root mean square difference is 0.74±0.59 Å for all heavy atoms. The resulting structure indicates an interesting feature in that the three C-terminal residues of bottromycin A(2) fold back on the 12-membered cyclic skeleton made by the four N-terminal residues. Thus, MePro(2) and Thia-β-Ala-OMe(7), modification of which significantly affects the antibacterial activities of bottromycin A(2), are located on one side of its 3D structure. These distinct structural features might be important for the binding of bottromycin A(2) with the bacterial ribosome.
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ABSTRACT: A large number of protein-protein interactions involved turn or loop regions. The excised linear peptides from these regions reveal complex conformational averaging. To circumvent this motional averaging and to stabilize the beta-turn conformation, extensive effort has been devoted to the design of constrained peptidomimetics. Here, we report the three-dimensional solution structure of a 12-membered cyclic peptidomimetic. The structures were calculated from NMR studies performed in chloroform and in water at 263 and 278K, respectively. This 12-membered cyclic scaffolding is part of a program to design and to construct conformationally stable beta-turn peptidomimetics. The impact of the surrounding environment on the conformation of this constrained peptidomimetic is discussed. The general structural features of the cyclic mimetic are retained in both environments; however, the formation of a hydrophobic patch in the aqueous solvent is evident.FEBS Letters 03/1995; 359(2-3):113-8. · 3.58 Impact Factor
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ABSTRACT: "Pseudo-structures" of the 20 common amino acid residues are introduced for use in protein spatial structure determinations, which rely on the use of intramolecular proton-proton distance constraints determined by nuclear Overhauser effects as input for distance geometry calculations. The proposed structures satisfy requirements for the initial structural interpretation of the nuclear magnetic resonance data that arise from the absence of stereospecific assignments and/or limited spectral resolution for certain resonance lines. The pseudo-atoms used as reference points for the experimental distance constraints can be used in conjunction with the real amino acid structures representing the van der Waals' constraints on the spatial molecular structure, or with simplified models in order to reduce the computing time for the distance geometry calculations.Journal of Molecular Biology 11/1983; 169(4):949-61. · 3.91 Impact Factor
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ABSTRACT: Oxazolidinones represent a new class of synthetic antibacterial agents active against multiply-resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci and vancomycin-resistant enterococci. Eperezolid and linezolid are two novel analogues, which have respectively completed Phase I and Phase II clinical testing. The lack of cross-resistance between oxazolidinones and other antibiotics supports a novel mechanism of action. Oxazolidinones are protein synthesis inhibitors which target an early step involving the binding of N-formylmethionyl-tRNA to the ribosome. Binding studies demonstrate that these agents interact with the 50S subunit, but not the 30S subunit of the ribosome. Crosslinking experiments provide evidence for an interaction with both the 16S rRNA of the small subunit and the 23S rRNA of the large subunit. Development of resistance in the laboratory is slow, resulting in two independently isolated point mutations at G2447U and G2576U of the 23S rRNA. This review discusses the results of published studies involving oxazolidinone mechanism of action.Expert Opinion on Investigational Drugs 09/1999; 8(8):1195-202. · 4.74 Impact Factor