Abstract:
:Bacterial tRNA-guanine transglycosylase (Tgt) is involved in the biosynthesis of the modified tRNA nucleoside queuosine present in the anticodon wobble position of tRNAs specific for aspartate, asparagine, histidine, and tyrosine. Inactivation of the tgt gene leads to decreased pathogenicity of Shigella bacteria. Therefore, Tgt constitutes a putative target for Shigellosis drug therapy. Since it is only active as homodimer, interference with dimer-interface formation may, in addition to active-site inhibition, provide further means to disable this protein. A cluster of four aromatic residues seems important to stabilize the homodimer. We mutated residues of this aromatic cluster and analyzed each mutated variant with respect to the dimer and thermal stability or enzyme activity by applying native mass spectrometry, a thermal shift assay, enzyme kinetics, and X-ray crystallography. Our structural studies indicate a strong influence of pH on the homodimer stability. Apparently, protonation of a histidine within the aromatic cluster supports the collapse of an essential structural motif within the dimer interface at slightly acidic pH.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Nguyen A,Nguyen D,Phong Nguyen TX,Sebastiani M,Dörr S,Hernandez-Alba O,Debaene F,Cianférani S,Heine A,Klebe G,Reuter Kdoi
10.1021/acschembio.0c00700subject
Has Abstractpub_date
2020-11-20 00:00:00pages
3021-3029issue
11eissn
1554-8929issn
1554-8937journal_volume
15pub_type
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