Crystal Structures of Penicillin-Binding Proteins 4 and 5 from Haemophilus influenzae

Fumihiro Kawai, Thomas B. Clarke, David I. Roper, Gab Jo Han, Kwang Yeon Hwang, Satoru Unzai, Eiji Obayashi, Sam Yong Park, Jeremy R.H. Tame

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20 Citations (Scopus)

Abstract

We have determined high-resolution apo crystal structures of two low molecular weight penicillin-binding proteins (PBPs), PBP4 and PBP5, from Haemophilus influenzae, one of the most frequently found pathogens in the upper respiratory tract of children. Novel β-lactams with notable antimicrobial activity have been designed, and crystal structures of PBP4 complexed with ampicillin and two of the novel molecules have also been determined. Comparing the apo form with those of the complexes, we find that the drugs disturb the PBP4 structure and weaken X-ray diffraction, to very different extents. PBP4 has recently been shown to act as a sensor of the presence of penicillins in Pseudomonas aeruginosa, and our models offer a clue to the structural basis for this effect. Covalently attached penicillins press against a phenylalanine residue near the active site and disturb the deacylation step. The ready inhibition of PBP4 by β-lactams compared to PBP5 also appears to be related to the weaker interactions holding key residues in a catalytically competent position.

Original languageEnglish
Pages (from-to)634-645
Number of pages12
JournalJournal of Molecular Biology
Volume396
Issue number3
DOIs
Publication statusPublished - 2010

Keywords

  • Antibiotic
  • Deacylation
  • Flexibility
  • Mechanism
  • Resistance

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Kawai, F., Clarke, T. B., Roper, D. I., Han, G. J., Hwang, K. Y., Unzai, S., Obayashi, E., Park, S. Y., & Tame, J. R. H. (2010). Crystal Structures of Penicillin-Binding Proteins 4 and 5 from Haemophilus influenzae. Journal of Molecular Biology, 396(3), 634-645. https://doi.org/10.1016/j.jmb.2009.11.055