1RP5

PBP2x from Streptococcus pneumoniae strain 5259 with reduced susceptibility to beta-lactam antibiotics

Summary for 1RP5

• Entry DOI: 10.2210/pdb1rp5/pdb
• Related: 1K25 1PMD 1PYY 1QME 1QMF
• Descriptor: penicillin-binding protein 2x, SULFATE ION (3 entities in total)
• Functional Keywords: penicillin-binding protein, transpeptidase, antibiotic resistance, peptidoglycan synthesis, cell wall, transmembrane
• Biological source: Streptococcus pneumoniae
• Cellular location: Cell membrane; Single-pass membrane protein: P14677
• Total number of polymer chains: 2
• Total formula weight: 154004.19

Authors

Pernot, L.,Chesnel, L.,Legouellec, A.,Croize, J.,Vernet, T.,Dideberg, O.,Dessen, A. (deposition date: 2003-12-03, release date: 2004-02-03, Last modification date: 2023-08-23)

Primary citation

Pernot, L.,Chesnel, L.,Le Gouellec, A.,Croize, J.,Vernet, T.,Dideberg, O.,Dessen, A.
A PBP2x from a clinical isolate of Streptococcus pneumoniae exhibits an alternative mechanism for reduction of susceptibility to beta-lactam antibiotics.
J.Biol.Chem., 279:16463-16470, 2004

PubMed Abstract: 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.

PubMed: 14734544
DOI: 10.1074/jbc.M313492200

Experimental method

X-RAY DIFFRACTION (3 Å)