Send to:

Choose Destination
See comment in PubMed Commons below
Structure. 2012 Oct 10;20(10):1681-91. doi: 10.1016/j.str.2012.07.011. Epub 2012 Aug 16.

Distinct states of methionyl-tRNA synthetase indicate inhibitor binding by conformational selection.

Author information

  • 1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.


To guide development of new drugs targeting methionyl-tRNA synthetase (MetRS) for treatment of human African trypanosomiasis, crystal structure determinations of Trypanosoma brucei MetRS in complex with its substrate methionine and its intermediate product methionyl-adenylate were followed by those of the enzyme in complex with high-affinity aminoquinolone inhibitors via soaking experiments. Drastic changes in conformation of one of the two enzymes in the asymmetric unit allowed these inhibitors to occupy an enlarged methionine pocket and a new so-called auxiliary pocket. Interestingly, a small low-affinity compound caused the same conformational changes, removed the methionine without occupying the methionine pocket, and occupied the previously not existing auxiliary pocket. Analysis of these structures indicates that the binding of the inhibitors is the result of conformational selection, not induced fit.

Copyright © 2012 Elsevier Ltd. All rights reserved.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk