Crystal structures of penicillin-binding proteins 4 and 5 from Haemophilus influenzae.
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 beta-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 beta-lactams compared to PBP5 also appears to be related to the weaker interactions holding key residues in a catalytically competent position.
Kawai
Fumihiro
F
Yokohama City University, Suehiro 1-7-29, Tsurumi, Yokohama 230-0045, Japan.
Clarke
Thomas B
TB
Roper
David I
DI
Han
Gab-Jo
GJ
Hwang
Kwang Yeon
KY
Unzai
Satoru
S
Obayashi
Eiji
E
Park
Sam-Yong
SY
Tame
Jeremy R H
JR
D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006193:Haemophilus influenzae / Q000737:chemistry / Q000201:enzymology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D046915:Penicillin-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D047090:beta-Lactams / Q000378:metabolism / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams