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A transferred NOE study of a tricyclic analog of acyclovir bound to thymidine kinase

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Summary

A purine derivative with an acyclic sugar analog, 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-6-ethyl-9-oxo-5H-imidazo[1,2-a]purine, was studied in the free state and in complex with herpes simplex virus thymidine kinase (HSV1 TK). Transferred NOE experiments, combined with a full relaxation matrix analysis of the substrate's spin system, resulted in a set of distance constraints for all proton pairs. These constraints were used in structure determination procedures based on simulated annealing and molecular dynamics simulations to obtain a family of structures compatible with the experimental NMR data. The results indicate that, although in both states the chains have the syn orientation with respect to the aromatic rings, in the free state the substrate's acyclic moiety is relatively disordered, while in the bound state only one specific conformation is preferred. Fluctuations can only be seen in the case of the terminal hydroxyl group, for which no NOE was recorded and hence no constraints were available.

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Authors and Affiliations

  1. Institut de Pharmacologie et de Biologie Structurale, CNRS, 118, route de Narbonne, F-31062, Toulouse, France

    Jerzy Czaplicki & Alain Milon

  2. Department Pharmazie, ETH Zürich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland

    Thomas Bohner & Gerd Folkers

  3. Institut für Pharmazie, Universität Leipzig, Brüderstrasse 34, D-04103, Leipzig, Germany

    Anne-Kathrin Habermann

Authors
  1. Jerzy Czaplicki
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  2. Thomas Bohner
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  3. Anne-Kathrin Habermann
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  4. Gerd Folkers
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  5. Alain Milon
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Czaplicki, J., Bohner, T., Habermann, AK. et al. A transferred NOE study of a tricyclic analog of acyclovir bound to thymidine kinase. J Biomol NMR 8, 261–272 (1996). https://doi.org/10.1007/BF00410325

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  • DOI: https://doi.org/10.1007/BF00410325

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