Abstract
Tenofovir is an acyclic phosphonate analog of deoxyadenylate used in AIDS and hepatitis B therapy. We find that tenofovir diphosphate, its active form, can be produced by human nucleoside diphosphate kinase (NDPK), but with low efficiency, and that creatine kinase is significantly more active. The 1.65 A x-ray structure of NDPK in complex with tenofovir mono- and diphosphate shows that the analogs bind at the same site as natural nucleotides, but in a different conformation, and make only a subset of the Van der Waals and polar interactions made by natural substrates, consistent with their comparatively low affinity for the enzyme.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemistry
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Adenine / pharmacology
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Antiviral Agents / pharmacology*
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Binding Sites
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Crystallography, X-Ray
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Dictyostelium / enzymology
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Escherichia coli / genetics
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Humans
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Models, Molecular
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Nucleoside-Diphosphate Kinase / chemistry*
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Nucleoside-Diphosphate Kinase / metabolism*
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Nucleotides / chemistry*
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Organophosphonates / chemistry*
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Organophosphonates / pharmacology
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Phosphorylation / drug effects
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology
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Substrate Specificity
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Tenofovir
Substances
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Antiviral Agents
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Nucleotides
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Organophosphonates
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Recombinant Proteins
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Reverse Transcriptase Inhibitors
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Tenofovir
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Nucleoside-Diphosphate Kinase
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Adenine