1pyy

Double mutant PBP2x T338A/M339F from Streptococcus pneumoniae strain R6 at 2.4 A resolution

spinqualitylabelsall models 1pyy, resolution 2.42Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1pyy is a 1 chain structure with sequence from Streptococcus pneumoniae R6. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.42Å Ligands: GLC, MPD, PRD_900045, SO4, TRV Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PBPX_STRR6 Penicillin-binding proteins (PBPs) function in the late steps of murein biosynthesis. Beta-lactams inactivate the PBPs by acylating an essential serine residue in the active site of these proteins. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Penicillin-binding protein 3D structures

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