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Structure of MurF from Streptococcus pneumoniae co-crystallized with a small molecule inhibitor exhibits interdomain

Kenton L Longenecker1, Geoffrey F Stamper, Philip J Hajduk

  • 1Department of Structural Biology, R46Y, Building AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA. Kenton.Longenecker@Abbott.com

Protein Science : a Publication of the Protein Society
|December 3, 2005
PubMed

Insights

Researchers identified MurF, a key enzyme in Streptococcus pneumoniae cell wall synthesis, as a potential antibiotic target. Structural studies revealed how an inhibitor binds, paving the way for new drug development against bacterial infections.

Area of Science:

  • Microbiology
  • Structural Biology
  • Drug Discovery

Background:

  • Genomics analysis identified MurF as an essential gene product in Streptococcus pneumoniae.
  • MurF catalyzes a critical reaction in peptidoglycan biosynthesis for bacterial cell wall formation.
  • MurF lacks mammalian homologs, making it an attractive target for novel antibiotics.

Purpose of the Study:

  • To investigate the structure of a MurF-inhibitor complex.
  • To provide a structural basis for structure-based drug design targeting MurF.
  • To assess MurF as a viable pharmaceutical target for antibiotic development.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy.
  • X-ray crystallography.
  • Small-molecule compound screening.

Main Results:

  • The multidomain structure of a MurF-inhibitor complex was determined.
  • The inhibitor binds to the substrate-binding region, inducing domain closure.
  • This conformation differs significantly from related structures and suggests a transition state arrangement.

Conclusions:

  • The MurF-inhibitor complex structure provides a foundation for optimizing lead compounds.
  • Structure-based design can be employed to develop MurF-targeting antibiotics.
  • MurF is a promising pharmaceutical target for combating bacterial infections.

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