1pyy
From Proteopedia
(New page: 200px<br /><applet load="1pyy" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pyy, resolution 2.42Å" /> '''Double mutant PBP2x ...) |
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| - | [[Image:1pyy.jpg|left|200px]]<br /><applet load="1pyy" size=" | + | [[Image:1pyy.jpg|left|200px]]<br /><applet load="1pyy" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1pyy, resolution 2.42Å" /> | caption="1pyy, resolution 2.42Å" /> | ||
'''Double mutant PBP2x T338A/M339F from Streptococcus pneumoniae strain R6 at 2.4 A resolution'''<br /> | '''Double mutant PBP2x T338A/M339F from Streptococcus pneumoniae strain R6 at 2.4 A resolution'''<br /> | ||
==Overview== | ==Overview== | ||
| - | PBP2x is a primary determinant of beta-lactams resistance in Streptococcus | + | PBP2x is a primary determinant of beta-lactams resistance in Streptococcus pneumoniae. Altered PBP2x with multiple mutations have a reduced "affinity" for the antibiotics. An important polymorphism is found in PBP2x sequences from clinical resistant strains. To understand the mechanism of resistance, it is necessary to identify and characterize the relevant substitutions. Many similar PBP2x sequences from resistant isolates have the previously studied T338A mutation, adjacent to the active site Ser337. We report here the structural and functional analysis of the M339F substitution that is found in a subset of these sequences, originating from highly resistant strains. The M339F mutation causes a 4-10-fold reduction of the reaction rate with beta-lactams, depending on the molecular context. In addition, release of the inactivated antibiotic from the active site is up to 3-fold faster as a result from the M339F mutation. These effects measured in vitro are correlated with the level of beta-lactam resistance in vivo conferred by several PBP2x variants. Thus, a single amino acid difference between similar PBP2x from clinical isolates can strongly modulate the degree of beta-lactam resistance. The crystal structure of the double mutant T338A/M339F solved to a resolution of 2.4 A shows a distortion of the active site and a reorientation of the hydroxyl group of the active site Ser337, which can explain the kinetic effects of the mutations. |
==About this Structure== | ==About this Structure== | ||
| - | 1PYY 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, OSU and MPD as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1PYY 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>, <scene name='pdbligand=OSU:'>OSU</scene> and <scene name='pdbligand=MPD:'>MPD</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PYY OCA]. |
==Reference== | ==Reference== | ||
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[[Category: transmembrane]] | [[Category: transmembrane]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:34:02 2008'' |
Revision as of 12:34, 21 February 2008
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Double mutant PBP2x T338A/M339F from Streptococcus pneumoniae strain R6 at 2.4 A resolution
Overview
PBP2x is a primary determinant of beta-lactams resistance in Streptococcus pneumoniae. Altered PBP2x with multiple mutations have a reduced "affinity" for the antibiotics. An important polymorphism is found in PBP2x sequences from clinical resistant strains. To understand the mechanism of resistance, it is necessary to identify and characterize the relevant substitutions. Many similar PBP2x sequences from resistant isolates have the previously studied T338A mutation, adjacent to the active site Ser337. We report here the structural and functional analysis of the M339F substitution that is found in a subset of these sequences, originating from highly resistant strains. The M339F mutation causes a 4-10-fold reduction of the reaction rate with beta-lactams, depending on the molecular context. In addition, release of the inactivated antibiotic from the active site is up to 3-fold faster as a result from the M339F mutation. These effects measured in vitro are correlated with the level of beta-lactam resistance in vivo conferred by several PBP2x variants. Thus, a single amino acid difference between similar PBP2x from clinical isolates can strongly modulate the degree of beta-lactam resistance. The crystal structure of the double mutant T338A/M339F solved to a resolution of 2.4 A shows a distortion of the active site and a reorientation of the hydroxyl group of the active site Ser337, which can explain the kinetic effects of the mutations.
About this Structure
1PYY is a Single protein structure of sequence from Streptococcus pneumoniae with , and as ligands. Full crystallographic information is available from OCA.
Reference
The structural modifications induced by the M339F substitution in PBP2x from Streptococcus pneumoniae further decreases the susceptibility to beta-lactams of resistant strains., Chesnel L, Pernot L, Lemaire D, Champelovier D, Croize J, Dideberg O, Vernet T, Zapun A, J Biol Chem. 2003 Nov 7;278(45):44448-56. Epub 2003 Aug 15. PMID:12923202
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