2jci
From Proteopedia
(New page: 200px<br /><applet load="2jci" size="350" color="white" frame="true" align="right" spinBox="true" caption="2jci, resolution 2.50Å" /> '''STRUCTURAL INSIGHTS ...) |
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==Overview== | ==Overview== | ||
| - | Class A penicillin-binding proteins (PBPs) catalyze the last two steps in | + | Class A penicillin-binding proteins (PBPs) catalyze the last two steps in the biosynthesis of peptidoglycan, a key component of the bacterial cell wall. Both reactions, glycosyl transfer (polymerization of glycan chains) and transpeptidation (cross-linking of stem peptides), are essential for peptidoglycan stability and for the cell division process, but remain poorly understood. The PBP-catalyzed transpeptidation reaction is the target of beta-lactam antibiotics, but their vast employment worldwide has prompted the appearance of highly resistant strains, thus requiring concerted efforts towards an understanding of the transpeptidation reaction with the goal of developing better antibacterials. This goal, however, has been elusive, since PBP substrates are rapidly deacylated. In this work, we provide a structural snapshot of a "trapped" covalent intermediate of the reaction between a class A PBP with a pseudo-substrate, N-benzoyl-D-alanylmercaptoacetic acid thioester, which partly mimics the stem peptides contained within the natural, membrane-associated substrate, lipid II. The structure reveals that the D-alanyl moiety of the covalent intermediate (N-benzoyl-d-alanine) is stabilized in the cleft by a network of hydrogen bonds that place the carbonyl group in close proximity to the oxyanion hole, thus mimicking the spatial arrangement of beta-lactam antibiotics within the PBP active site. This arrangement allows the target bond to be in optimal position for attack by the acceptor peptide and is similar to the structural disposition of beta-lactam antibiotics with PBP clefts. This information yields a better understanding of PBP catalysis and could provide key insights into the design of novel PBP inhibitors. |
==About this Structure== | ==About this Structure== | ||
| - | 2JCI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptococcus_pneumoniae_r6 Streptococcus pneumoniae r6] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=S2D:'>S2D</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Sites: <scene name='pdbsite=AC1:S2d Binding Site For Chain A'>AC1</scene>, <scene name='pdbsite=AC2:S2d Binding Site For Chain B'>AC2</scene>, <scene name='pdbsite=AC3:So4 Binding Site For Chain B'>AC3</scene>, <scene name='pdbsite=AC4:So4 Binding Site For Chain A'>AC4</scene>, <scene name='pdbsite=AC5:Cl Binding Site For Chain A'>AC5</scene> and <scene name='pdbsite=AC6:Cl Binding Site For Chain A'>AC6</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JCI OCA]. | + | 2JCI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptococcus_pneumoniae_r6 Streptococcus pneumoniae r6] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=S2D:'>S2D</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Sites: <scene name='pdbsite=AC1:S2d+Binding+Site+For+Chain+A'>AC1</scene>, <scene name='pdbsite=AC2:S2d+Binding+Site+For+Chain+B'>AC2</scene>, <scene name='pdbsite=AC3:So4+Binding+Site+For+Chain+B'>AC3</scene>, <scene name='pdbsite=AC4:So4+Binding+Site+For+Chain+A'>AC4</scene>, <scene name='pdbsite=AC5:Cl+Binding+Site+For+Chain+A'>AC5</scene> and <scene name='pdbsite=AC6:Cl+Binding+Site+For+Chain+A'>AC6</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JCI OCA]. |
==Reference== | ==Reference== | ||
| - | Trapping of an | + | Trapping of an acyl-enzyme intermediate in a penicillin-binding protein (PBP)-catalyzed reaction., Macheboeuf P, Lemaire D, Martins Ados S, Dideberg O, Jamin M, Dessen A, J Mol Biol. 2008 Feb 15;376(2):405-13. Epub 2007 Nov 1. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18155726 18155726] |
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Streptococcus pneumoniae r6]] | [[Category: Streptococcus pneumoniae r6]] | ||
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[[Category: pseudo-substrate]] | [[Category: pseudo-substrate]] | ||
| - | ''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 18:01:41 2008'' |
Revision as of 16:01, 21 February 2008
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STRUCTURAL INSIGHTS INTO THE CATALYTIC MECHANISM AND THE ROLE OF STREPTOCOCCUS PNEUMONIAE PBP1B
Overview
Class A penicillin-binding proteins (PBPs) catalyze the last two steps in the biosynthesis of peptidoglycan, a key component of the bacterial cell wall. Both reactions, glycosyl transfer (polymerization of glycan chains) and transpeptidation (cross-linking of stem peptides), are essential for peptidoglycan stability and for the cell division process, but remain poorly understood. The PBP-catalyzed transpeptidation reaction is the target of beta-lactam antibiotics, but their vast employment worldwide has prompted the appearance of highly resistant strains, thus requiring concerted efforts towards an understanding of the transpeptidation reaction with the goal of developing better antibacterials. This goal, however, has been elusive, since PBP substrates are rapidly deacylated. In this work, we provide a structural snapshot of a "trapped" covalent intermediate of the reaction between a class A PBP with a pseudo-substrate, N-benzoyl-D-alanylmercaptoacetic acid thioester, which partly mimics the stem peptides contained within the natural, membrane-associated substrate, lipid II. The structure reveals that the D-alanyl moiety of the covalent intermediate (N-benzoyl-d-alanine) is stabilized in the cleft by a network of hydrogen bonds that place the carbonyl group in close proximity to the oxyanion hole, thus mimicking the spatial arrangement of beta-lactam antibiotics within the PBP active site. This arrangement allows the target bond to be in optimal position for attack by the acceptor peptide and is similar to the structural disposition of beta-lactam antibiotics with PBP clefts. This information yields a better understanding of PBP catalysis and could provide key insights into the design of novel PBP inhibitors.
About this Structure
2JCI 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
Trapping of an acyl-enzyme intermediate in a penicillin-binding protein (PBP)-catalyzed reaction., Macheboeuf P, Lemaire D, Martins Ados S, Dideberg O, Jamin M, Dessen A, J Mol Biol. 2008 Feb 15;376(2):405-13. Epub 2007 Nov 1. PMID:18155726
Page seeded by OCA on Thu Feb 21 18:01:41 2008
