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Structure of Pseudomonas aeruginosa inosine 5'-monophosphate dehydrogenase

Vincenzo A Rao1, Sharon M Shepherd, Richard Owen

  • 1Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland.

Acta Crystallographica. Section F, Structural Biology and Crystallization Communications
|March 23, 2013
PubMed

Insights

The crystal structure of Pseudomonas aeruginosa IMPDH was determined, revealing a conserved active site crucial for its potential as an antimicrobial drug target against bacterial and protozoan infections.

Area of Science:

  • Structural Biology
  • Biochemistry
  • Antimicrobial Drug Discovery

Background:

  • Inosine 5'-monophosphate dehydrogenase (IMPDH) is a validated antimicrobial drug target.
  • Understanding the structure of bacterial IMPDH is key to developing selective inhibitors.

Purpose of the Study:

  • To determine the crystal structure of recombinant Pseudomonas aeruginosa IMPDH.
  • To analyze structural features relevant to substrate and cofactor binding.
  • To assess the potential of P. aeruginosa IMPDH as a drug target.

Main Methods:

  • X-ray crystallography was used to determine the structure of P. aeruginosa IMPDH to 2.25 Å resolution.
  • Homology modeling and sequence analysis were employed to compare with other IMPDH structures.

Main Results:

  • The structure revealed a homotetramer with a (β/α)8-barrel fold, common to IMPDH enzymes.
  • A distinct loop (residues 297-315) forming part of the active site, including catalytic Cys304, was clearly defined.
  • Key residues for substrate and NAD+ cofactor binding are conserved, as are selectivity-conferring differences found in other IMPDHs.

Conclusions:

  • The determined structure provides insights into the catalytic mechanism and active site of P. aeruginosa IMPDH.
  • Conserved residues important for selectivity suggest P. aeruginosa IMPDH is a promising target for novel antimicrobial drug development.
Keywords:
Pseudomonas aeruginosaantimicrobial drug targetsinosine 5′-monophosphate dehydrogenase

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