Comparison of ligand-induced conformational changes and domain closure mechanisms, between prokaryotic and eukaryotic dehydroquinate synthases.
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.
Nichols
C E
CE
Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Ren
J
J
Leslie
K
K
Dhaliwal
B
B
Lockyer
M
M
Charles
I
I
Hawkins
A R
AR
Stammers
D K
DK
D000595:Amino Acid Sequence; D001233:Aspergillus nidulans / Q000201:enzymology; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005057:Eukaryotic Cells / Q000201:enzymology*; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D063065:Organophosphonates / Q000737:chemistry; D019761:Phosphorus-Oxygen Lyases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011387:Prokaryotic Cells / Q000201:enzymology*; D011487:Protein Conformation; D016415:Sequence Alignment; D013211:Staphylococcus aureus / Q000201:enzymology
D001426:Bacterial Proteins; D005656:Fungal Proteins; D008024:Ligands; D046911:Macromolecular Substances; D063065:Organophosphonates; D009243:NAD; C020001:3-dehydroquinate synthetase; D019761:Phosphorus-Oxygen Lyases