title: Nucleoside diphosphate kinase and the activation of antiviral phosphonate analogs of nucleotides: binding mode and phosphorylation of tenofovir derivatives.
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.
authors.affiliation: Yeast Structural Genomics, IBBMC UMR 8619 CNRS, Universite Paris-Sud, Orsay, France.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Koch
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Chen
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Feng
authors.forename: Katyna
authors.initials: K
authors.lastname: Borroto-Esoda
authors.forename: Dominique
authors.initials: D
authors.lastname: Deville-Bonne
authors.forename: Sarah
authors.initials: S
authors.lastname: Gallois-Montbrun
authors.forename: Joël
authors.initials: J
authors.lastname: Janin
authors.forename: Solange
authors.initials: S
authors.lastname: Moréra
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004023:Dictyostelium / Q000201:enzymology; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009701:Nucleoside-Diphosphate Kinase / Q000737:chemistry* / Q000378:metabolism*; D009711:Nucleotides / Q000737:chemistry*; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013379:Substrate Specificity; D000068698:Tenofovir
chemical_list: D000998:Antiviral Agents; D009711:Nucleotides; D063065:Organophosphonates; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D009701:Nucleoside-Diphosphate Kinase; D000225:Adenine