Abstract
Neighboring-group participation in the reaction catalyzed by purine nucleoside phosphorylase involves a compression mode between the 5'- and 4'-ribosyl oxygens, facilitated by His257. The His257Gly mutant opens a space in the catalytic site. Hydrophobic 5'-substituted Immucillins are transition-state analogue inhibitors of this mutant enzyme. Dissociation constants as low as 2pM are achieved, with K(m)/K(d) as high as 400,000,000.
MeSH terms
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Catalytic Domain*
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Crystallography, X-Ray
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Glycine / chemistry
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Glycine / genetics
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Histidine / chemistry
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Histidine / genetics
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Humans
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Imidazoles / chemistry
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Kinetics
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Mutation
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Protein Conformation
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Purine Nucleosides / chemistry*
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Purine-Nucleoside Phosphorylase* / chemistry
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Purine-Nucleoside Phosphorylase* / genetics
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Purine-Nucleoside Phosphorylase* / metabolism
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Pyrimidinones / chemistry*
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Structure-Activity Relationship
Substances
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Imidazoles
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Purine Nucleosides
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Pyrimidinones
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forodesine
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Histidine
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Purine-Nucleoside Phosphorylase
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Glycine