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Crystal structure of the Streptococcus pneumoniae mevalonate kinase in complex with diphosphomevalonate

John L Andreassi1, Patrick W Bilder, Matthew W Vetting

  • 1DuPont Crop Protection, Stine-Haskell Research Center, Newark, Delaware 19711, USA.

Protein Science : a Publication of the Protein Society
|April 3, 2007
PubMed

Insights

Researchers crystallized Streptococcus pneumoniae mevalonate kinase (SpMK) bound to diphosphomevalonate (DPM). This reveals a novel target for developing new antimicrobials against drug-resistant bacteria.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Microbiology

Background:

  • Streptococcus pneumoniae is a major cause of bacterial infections with increasing antimicrobial resistance.
  • The isoprenoid biosynthesis pathway is essential for bacterial survival.
  • Diphosphomevalonate (DPM) was identified as a potent inhibitor of S. pneumoniae mevalonate kinase (SpMK).

Purpose of the Study:

  • To determine the crystal structure of S. pneumoniae mevalonate kinase (SpMK) in complex with DPM.
  • To understand the mechanism of DPM inhibition.
  • To provide insights for novel antimicrobial drug design.

Main Methods:

  • X-ray crystallography
  • Protein structure determination
  • Biochemical assays

Main Results:

  • The crystal structure of SpMK complexed with DPM.Mg(2+) was determined at 2.5 A resolution.
  • DPM binds to the active-site cleft of SpMK, acting as a partial bisubstrate analog.
  • Structural comparisons revealed unique features of SpMK compared to other GHMP kinases.

Conclusions:

  • The SpMK-DPM structure provides a blueprint for designing targeted antimicrobials.
  • Inhibition of SpMK represents a promising strategy against drug-resistant S. pneumoniae.
  • Understanding SpMK structure-function relationships may inform studies of related human diseases.

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