Abstract
The crystal structures of the type II dehydroquinase (DHQase) from Helicobacter pylori in complex with three competitive inhibitors have been determined. The inhibitors are the substrate analogue 2,3-anhydroquinate (FA1), citrate, and an oxoxanthene sulfonamide derivative (AH9095). Despite the very different chemical nature of the inhibitors, in each case the primary point of interaction with the enzyme is via the residues that bind the C1 functionalities of the substrate, 3-dehydroquinate, i.e., N76, H102, I103, and H104. The DHQase/AH9095 complex crystal structure shows that sulfonamides can form a scaffold for nonsubstrate-like inhibitors and identifies a large conserved hydrophobic patch at the entrance to the active site as a locus that can be exploited in the development of new ligands.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Anti-Bacterial Agents / chemistry*
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Anti-Bacterial Agents / pharmacology
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Binding Sites
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Citric Acid / chemistry
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Citric Acid / pharmacology
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Crystallography, X-Ray
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Drug Design
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Escherichia coli / drug effects
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Escherichia coli / genetics
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Helicobacter pylori / enzymology*
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Hydro-Lyases / antagonists & inhibitors*
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Hydro-Lyases / chemistry*
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Kinetics
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Ligands
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Models, Molecular
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Molecular Sequence Data
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Molecular Structure
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Mycobacterium tuberculosis / enzymology
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Quinic Acid / analogs & derivatives
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Quinic Acid / chemistry
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Quinic Acid / pharmacology
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Sequence Alignment
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Streptomyces coelicolor / enzymology
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Structure-Activity Relationship
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Tetrazoles / chemistry*
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Tetrazoles / pharmacology
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Xanthones / chemistry*
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Xanthones / pharmacology
Substances
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2,3-anhydroquinic acid
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3-dehydroquinic acid
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Anti-Bacterial Agents
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Ligands
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N-tetrazol-5-yl-9-oxo-9H-xanthene-2-sulfonamide
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Tetrazoles
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Xanthones
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Quinic Acid
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Citric Acid
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Hydro-Lyases
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3-dehydroquinate dehydratase