2jch
From Proteopedia
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==Overview== | ==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== | ==About this Structure== | ||
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==Reference== | ==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 | + | 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 Sep;3(9):565-9. Epub 2007 Aug 5. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17676039 17676039] |
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Streptococcus pneumoniae r6]] | [[Category: Streptococcus pneumoniae r6]] | ||
| - | [[Category: Brown, T | + | [[Category: Brown, T J.]] |
[[Category: Dessen, A.]] | [[Category: Dessen, A.]] | ||
| - | [[Category: Fisher, D | + | [[Category: Fisher, D S.]] |
[[Category: Joris, B.]] | [[Category: Joris, B.]] | ||
[[Category: Luxen, A.]] | [[Category: Luxen, A.]] | ||
[[Category: Macheboeuf, P.]] | [[Category: Macheboeuf, P.]] | ||
| - | [[Category: Schofield, C | + | [[Category: Schofield, C J.]] |
[[Category: Zervosen, A.]] | [[Category: Zervosen, A.]] | ||
[[Category: CL]] | [[Category: CL]] | ||
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[[Category: peptidoglycan synthesis multifunctional enzyme]] | [[Category: peptidoglycan synthesis multifunctional enzyme]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:01:43 2008'' |
Revision as of 16:01, 21 February 2008
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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 , , and 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 Sep;3(9):565-9. Epub 2007 Aug 5. PMID:17676039
Page seeded by OCA on Thu Feb 21 18:01:43 2008
Categories: Single protein | Streptococcus pneumoniae r6 | Brown, T J. | Dessen, A. | Fisher, D S. | Joris, B. | Luxen, A. | Macheboeuf, P. | Schofield, C J. | Zervosen, A. | CL | EDO | PL7 | SO4 | Binding protein | Cell wall | Drug-binding protein | Gamma lactam antibiotics | Peptidoglycan | Peptidoglycan synthesis multifunctional enzyme
