2jch

From Proteopedia

Revision as of 17:50, 18 December 2007

STRUCTURAL AND MECHANISTIC BASIS OF PENICILLIN BINDING PROTEIN INHIBITION BY LACTIVICINS

Overview

beta-lactam antibiotics, including penicillins and cephalosporins, inhibit, penicillin-binding proteins (PBPs), which are essential for bacterial cell, wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic, resistance mechanisms that, in Gram-positive bacteria, include mutations, to PBPs that enable them to avoid beta-lactam inhibition. Lactivicin (LTV;, 1) contains separate cycloserine and gamma-lactone rings and is the only, known natural PBP inhibitor that does not contain a beta-lactam. Here we, show that LTV and a more potent analog, phenoxyacetyl-LTV (PLTV; 2), are, active against clinically isolated, penicillin-resistant Streptococcus, pneumoniae strains. Crystallographic analyses of S. pneumoniae PBP1b, reveal that LTV and PLTV inhibition involves opening of both monocyclic, cycloserine and gamma-lactone rings. In PBP1b complexes, the ring-derived, atoms from LTV and PLTV show a notable structural convergence with those, derived from a complexed cephalosporin (cefotaxime; 3). The structures, imply that derivatives of LTV will be useful in the search for new, antibiotics with activity against beta-lactam-resistant bacteria.

About this Structure

2JCH is a Single protein structure of sequence from Streptococcus pneumoniae r6 with SO4, CL, EDO and PL7 as ligands. Known structural/functional Sites: , , and . Full crystallographic information is available from OCA.

Reference

Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins., Macheboeuf P, Fischer DS, Brown T Jr, Zervosen A, Luxen A, Joris B, Dessen A, Schofield CJ, Nat Chem Biol. 2007 Aug 5;. PMID:17676039

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