Nucleoside Diphosphate Kinase and the Activation of Antiviral Phosphonate Analogs of Nucleotides: Binding Mode and Phosphorylation of Tenofovir Derivatives |
| |
| Authors: | Kerstin Koch Yuxing Chen Joy Y. Feng Katyna Borroto-Esoda Dominique Deville-Bonne Joël Janin |
| |
| Affiliation: | 1. Yeast Structural Genomics, IBBMC UMR 8619 CNRS , Université Paris-Sud , Orsay, France;2. Hefei National Laboratory for Physical Sciences at Microscale, and School of Life Sciences , University of Science and Technology of China , Hefei, Anhui, China;3. Gilead Sciences Inc. , Foster City, California, USA;4. Enzymologie Moléculaire , UR4 Université Pierre et Marie Curie , Paris, France |
| |
| 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 Å 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. |
| |
| Keywords: | |
|
|
