1rp5
From Proteopedia
(New page: 200px<br /><applet load="1rp5" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rp5, resolution 3.0Å" /> '''PBP2x from Streptococ...) |
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| - | [[Image:1rp5.jpg|left|200px]]<br /><applet load="1rp5" size=" | + | [[Image:1rp5.jpg|left|200px]]<br /><applet load="1rp5" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1rp5, resolution 3.0Å" /> | caption="1rp5, resolution 3.0Å" /> | ||
'''PBP2x from Streptococcus pneumoniae strain 5259 with reduced susceptibility to beta-lactam antibiotics'''<br /> | '''PBP2x from Streptococcus pneumoniae strain 5259 with reduced susceptibility to beta-lactam antibiotics'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The human pathogen Streptococcus pneumoniae is one of the main causative | + | The human pathogen Streptococcus pneumoniae is one of the main causative agents of respiratory tract infections. At present, clinical isolates of S. pneumoniae often exhibit decreased susceptibility toward beta-lactams, a phenomenon linked to multiple mutations within the penicillin-binding proteins (PBPs). PBP2x, one of the six PBPs of S. pneumoniae, is the first target to be modified under antibiotic pressure. By comparing 89 S. pneumoniae PBP2x sequences from clinical and public data bases, we have identified one major group of sequences from drug-sensitive strains as well as two distinct groups from drug-resistant strains. The first group includes proteins that display high similarity to PBP2x from the well characterized resistant strain Sp328. The second group includes sequences in which a signature mutation, Q552E, is found adjacent to the third catalytic motif. In this work, a PBP2x from a representative strain from the latter group (S. pneumoniae 5259) was biochemically and structurally characterized. Phenotypical analyses of transformed pneumococci show that the Q552E substitution is responsible for most of the reduction of strain susceptibility toward beta-lactams. The crystal structure of 5259-PBP2x reveals a change in polarity and charge distribution around the active site cavity, as well as rearrangement of strand beta3, emulating structural changes observed for other PBPs that confer drug resistance to Gram-positive pathogens. Interestingly, the active site of 5259-PBP2x is in closed conformation, whereas that of Sp328-PBP2x is open. Consequently, S. pneumoniae has evolved to employ the same protein in two distinct mechanisms of antibiotic resistance. |
==About this Structure== | ==About this Structure== | ||
| - | 1RP5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptococcus_pneumoniae Streptococcus pneumoniae] with SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1RP5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptococcus_pneumoniae Streptococcus pneumoniae] with <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RP5 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: transpeptidase]] | [[Category: transpeptidase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:53:08 2008'' |
Revision as of 12:53, 21 February 2008
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PBP2x from Streptococcus pneumoniae strain 5259 with reduced susceptibility to beta-lactam antibiotics
Overview
The human pathogen Streptococcus pneumoniae is one of the main causative agents of respiratory tract infections. At present, clinical isolates of S. pneumoniae often exhibit decreased susceptibility toward beta-lactams, a phenomenon linked to multiple mutations within the penicillin-binding proteins (PBPs). PBP2x, one of the six PBPs of S. pneumoniae, is the first target to be modified under antibiotic pressure. By comparing 89 S. pneumoniae PBP2x sequences from clinical and public data bases, we have identified one major group of sequences from drug-sensitive strains as well as two distinct groups from drug-resistant strains. The first group includes proteins that display high similarity to PBP2x from the well characterized resistant strain Sp328. The second group includes sequences in which a signature mutation, Q552E, is found adjacent to the third catalytic motif. In this work, a PBP2x from a representative strain from the latter group (S. pneumoniae 5259) was biochemically and structurally characterized. Phenotypical analyses of transformed pneumococci show that the Q552E substitution is responsible for most of the reduction of strain susceptibility toward beta-lactams. The crystal structure of 5259-PBP2x reveals a change in polarity and charge distribution around the active site cavity, as well as rearrangement of strand beta3, emulating structural changes observed for other PBPs that confer drug resistance to Gram-positive pathogens. Interestingly, the active site of 5259-PBP2x is in closed conformation, whereas that of Sp328-PBP2x is open. Consequently, S. pneumoniae has evolved to employ the same protein in two distinct mechanisms of antibiotic resistance.
About this Structure
1RP5 is a Single protein structure of sequence from Streptococcus pneumoniae with as ligand. Full crystallographic information is available from OCA.
Reference
A PBP2x from a clinical isolate of Streptococcus pneumoniae exhibits an alternative mechanism for reduction of susceptibility to beta-lactam antibiotics., Pernot L, Chesnel L, Le Gouellec A, Croize J, Vernet T, Dideberg O, Dessen A, J Biol Chem. 2004 Apr 16;279(16):16463-70. Epub 2004 Jan 20. PMID:14734544
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