Swapping Interface Contacts in the Homodimeric tRNA-Guanine Transglycosylase: An Option for Functional Regulation.

Abstract

The enzyme tRNA-guanine transglycosylase, a target to fight Shigellosis, recognizes tRNA only as a homodimer and performs full nucleobase exchange at the wobble position. Active-site inhibitors block the enzyme function by competitively replacing tRNA. In solution, the wild-type homodimer dissociates only marginally, whereas mutated variants show substantial monomerization in solution. Surprisingly, one inhibitor transforms the protein into a twisted state, whereby one monomer unit rotates by approximately 130°. In this altered geometry, the enzyme is no longer capable of binding and processing tRNA. Three sugar-type inhibitors have been designed and synthesized, which bind to the protein in either the functionally competent or twisted inactive state. They crystallize with the enzyme side-by-side under identical conditions from the same crystallization well. Possibly, the twisted inactive form corresponds to a resting state of the enzyme, important for its functional regulation.

• Authors: Frederik Rainer Ehrmann, Jorna Kalim, Toni Pfaffeneder, Bruno Bernet, Christoph Hohn, Elisabeth Schäfer, Thomas Botzanowski, Sarah Cianférani, Andreas Heine, Klaus Reuter, François Diederich, Gerhard Klebe
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 57 Issue 32 Pg. 10085-10090 (08 06 2018) ISSN: 1521-3773 [Electronic] Germany
• PMID: 29927035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Enzyme Inhibitors
• Pentosyltransferases
• queuine tRNA-ribosyltransferase

Topics

• Enzyme Inhibitors (chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Pentosyltransferases (antagonists & inhibitors, chemistry, metabolism)