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Swapping Interface Contacts in the Homodimeric tRNA‐Guanine Transglycosylase: An Option for Functional Regulation
Author(s) -
Ehrmann Frederik Rainer,
Kalim Jorna,
Pfaffeneder Toni,
Bernet Bruno,
Hohn Christoph,
Schäfer Elisabeth,
Botzanowski Thomas,
Cianférani Sarah,
Heine Andreas,
Reuter Klaus,
Diederich François,
Klebe Gerhard
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201804627
Subject(s) - guanine , transfer rna , enzyme , chemistry , nucleobase , wobble base pair , biochemistry , stereochemistry , rna , nucleotide , dna , gene
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.