Nucleoside diphosphate kinase and the activation of antiviral phosphonate analogs of nucleotides: binding mode and phosphorylation of tenofovir derivatives.
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.
Koch
Kerstin
K
Yeast Structural Genomics, IBBMC UMR 8619 CNRS, Universite Paris-Sud, Orsay, France.
Chen
Yuxing
Y
Feng
Joy Y
JY
Borroto-Esoda
Katyna
K
Deville-Bonne
Dominique
D
Gallois-Montbrun
Sarah
S
Janin
Joël
J
Moréra
Solange
S
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
D000998:Antiviral Agents; D009711:Nucleotides; D063065:Organophosphonates; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D009701:Nucleoside-Diphosphate Kinase; D000225:Adenine