PDBsum entry 2jch

Drug-binding protein

PDB id: 2jch

Contents

Protein chain

461 a.a. *

Ligands

SO4

EDO

PL7

Metals

_CL

Waters ×147

* Residue conservation analysis

PDB id:

2jch

Name:

Drug-binding protein

Title:

Structural and mechanistic basis of penicillin binding protein inhibition by lactivicins

Structure:

Penicillin-binding protein 1b. Chain: a. Fragment: residues 72-791. Engineered: yes. Mutation: yes

Source:

Streptococcus pneumoniae. Organism_taxid: 171101. Strain: r6. Atcc: baa-255. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.40Å R-factor: 0.206 R-free: 0.262

Authors:

P.Macheboeuf,D.S.Fisher,T.J.Brown,A.Zervosen,A.Luxen,B.Joris, A.Dessen,C.J.Schofield

Key ref:

P.Macheboeuf et al. (2007). Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins. Nat Chem Biol, 3, 565-569. PubMed id: 17676039 DOI: 10.1038/nchembio.2007.21

Date:

23-Dec-06 Release date: 14-Aug-07

Protein chain

O70038  (O70038_STREE) -  peptidoglycan glycosyltransferase from Streptococcus pneumoniae

Seq: 821 a.a.

Struc: 461 a.a.*

* PDB and UniProt seqs differ at 12 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.4.99.28 - peptidoglycan glycosyltransferase.
• Reaction: [GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)](n)- di-trans,octa-cis-undecaprenyl diphosphate + beta-D-GlcNAc-(1->4)- Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-di-trans,octa- cis-undecaprenyl diphosphate = [GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D- Glu-L-Lys-D-Ala-D-Ala)](n+1)-di-trans,octa-cis-undecaprenyl diphosphate + di-trans,octa-cis-undecaprenyl diphosphate + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

DOI no: 10.1038/nchembio.2007.21

Nat Chem Biol 3:565-569 (2007)

PubMed id: 17676039

Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins.

P.Macheboeuf, D.S.Fischer, T.Brown, A.Zervosen, A.Luxen, B.Joris, A.Dessen, C.J.Schofield.

ABSTRACT

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.

Selected figure(s)

Figure 1.
(a) Structures of -lactam antibiotics. The conserved -lactam ring is highlighted in green. (b) Structures of epimeric LTV and PLTV. (c) Outline mechanism for -lactams showing formation of the hydrolytically stable acyl-enzyme complex (for cefotaxime: R, aminothiazolemethoxyoxime; X, OCOCH[3]). (d) Proposed mechanism of PBP acylation by LTV and PLTV, involving formation of a stable acyl-enzyme complex whose structure is closely analogous to that formed by cephalosporins.

Figure 3.
(a) F[o] – F[c] map (green) contoured at 2.4 , generated before inclusion of LTV in the model. (b) F[o] – F[c] map (green), contoured at 2.4 , for the PLTV molecule. Selected active site residues are shown as sticks; LTV and PLTV backbones are shown in blue. Notably, ester link is present between the Ser460 side chain and the carbonyl of the LTV/PLTV cycloserine ring, and both cycloserine and lactone rings of the inhibitors are open. Figure was prepared using PyMOL (http://pymol.sourceforge.net/).

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2007, 3, 565-569) copyright 2007.

Figures were selected by an automated process.