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Crystal structures of penicillin-binding protein 3 (PBP3) from methicillin-resistant Staphylococcus aureus in the apo

Hisashi Yoshida1, Fumihiro Kawai, Eiji Obayashi

  • 1Protein Design Laboratory, Yokohama City University, Suehiro 1-7-29, Tsurumi-ku, Yokohama 230-0045, Japan.

Journal of Molecular Biology
|August 1, 2012
PubMed

Insights

Structural insights into methicillin-resistant Staphylococcus aureus penicillin-binding protein 3 (PBP3) reveal its unique domain orientation and monomeric state in solution, despite crystal structure suggesting dimerization. This aids in understanding antibiotic resistance mechanisms.

Area of Science:

  • Microbiology
  • Structural Biology
  • Biochemistry

Background:

  • Staphylococcus aureus, particularly methicillin-resistant strains (MRSA), poses significant clinical challenges due to antibiotic resistance.
  • Penicillin-binding proteins (PBPs) are crucial targets for β-lactam antibiotics, but their structural and functional characterization is key to developing new treatments.

Purpose of the Study:

  • To elucidate the structural characteristics of penicillin-binding protein 3 (PBP3) from MRSA.
  • To investigate the oligomeric state of PBP3 in solution and its implications for antibiotic binding.

Main Methods:

  • X-ray crystallography was employed to determine the structures of apo-PBP3 and PBP3 complexed with cefotaxime.
  • Electrospray mass spectrometry and analytical ultracentrifugation were used to assess the protein's behavior in solution.

Main Results:

  • Two crystal structures of MRSA PBP3 were solved, revealing a distinct domain orientation and a novel, larger N-terminal domain compared to other class B PBPs.
  • The crystal structure suggested a stable dimeric form of PBP3, driven by interactions of the N-terminal domain.
  • Mass spectrometry and ultracentrifugation confirmed that PBP3 exists as a monomer in solution, contradicting the crystal packing observations.

Conclusions:

  • MRSA PBP3 exhibits a unique structural arrangement with a potentially important N-terminal domain.
  • Despite crystal lattice suggesting dimerization, PBP3 functions as a monomer in solution, which is critical for understanding its interaction with antibiotics and resistance mechanisms.

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