Comparison of ligand-induced conformational changes and domain closure mechanisms, between prokaryotic and eukaryotic dehydroquinate synthases

J Mol Biol. 2004 Oct 22;343(3):533-46. doi: 10.1016/j.jmb.2004.08.039.


Dehydroquinate synthase (DHQS) is a potential target for the development of novel broad-spectrum antimicrobial drugs, active against both prokaryotes and lower eukaryotes. Structures have been reported for Aspergillus nidulans DHQS (AnDHQS) in complexes with a range of ligands. Analysis of these AnDHQS structures showed that a large-scale domain movement occurs during the normal catalytic cycle, with a complex series of structural elements propagating substrate binding-induced conformational changes away from the active site to distal locations. Compared to corresponding fungal enzymes, DHQS from bacterial species are both mono-functional and significantly smaller. We have therefore determined the structure of Staphylococcus aureus DHQS (SaDHQS) in five liganded states, allowing comparison of ligand-induced conformational changes and mechanisms of domain closure between fungal and bacterial enzymes. This comparative analysis shows that substrate binding initiates a large-scale domain closure in both species' DHQS and that the active site stereochemistry, of the catalytically competent closed-form enzyme thus produced, is also highly conserved. However, comparison of AnDHQS and SaDHQS open-form structures, and analysis of the putative dynamic processes by which the transition to the closed-form states are made, shows a far lower degree of similarity, indicating a significant structural divergence. As a result, both the nature of the propagation of conformational change and the mechanical systems involved in this propagation are quite different between the DHQSs from the two species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Aspergillus nidulans / enzymology
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Eukaryotic Cells / enzymology*
  • Fungal Proteins / chemistry
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Ligands
  • Macromolecular Substances
  • Models, Molecular
  • Molecular Sequence Data
  • NAD / chemistry
  • NAD / metabolism
  • Organophosphonates / chemistry
  • Phosphorus-Oxygen Lyases / chemistry*
  • Phosphorus-Oxygen Lyases / genetics
  • Phosphorus-Oxygen Lyases / metabolism
  • Prokaryotic Cells / enzymology*
  • Protein Conformation*
  • Sequence Alignment
  • Staphylococcus aureus / enzymology


  • Bacterial Proteins
  • Fungal Proteins
  • Ligands
  • Macromolecular Substances
  • Organophosphonates
  • NAD
  • 3-dehydroquinate synthetase
  • Phosphorus-Oxygen Lyases

Associated data

  • PDB/1XAG
  • PDB/1XAH
  • PDB/1XAI
  • PDB/1XAJ
  • PDB/1XAL