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https://hdl.handle.net/2440/117899
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Type: | Journal article |
Title: | Precipitant-ligand exchange technique reveals the ADP binding mode in Mycobacterium tuberculosis dethiobiotin synthetase |
Author: | Thompson, A. Wegener, K. Booker, G. Polyak, S. Bruning, J. |
Citation: | Acta Crystallographica Section D: Structural Biology, 2018; 74(10):965-972 |
Publisher: | Wiley |
Issue Date: | 2018 |
ISSN: | 2059-7983 2059-7983 |
Statement of Responsibility: | Andrew P. Thompson, Kate L. Wegener, Grant W. Booker, Steven W. Polyak and John B. Bruning |
Abstract: | Dethiobiotin synthetase from Mycobacterium tuberculosis (MtDTBS) is a promising antituberculosis drug target. Small-molecule inhibitors that target MtDTBS provide a route towards new therapeutics for the treatment of antibiotic-resistant tuberculosis. Adenosine diphosphate (ADP) is an inhibitor of MtDTBS; however, structural studies into its mechanism of inhibition have been unsuccessful owing to competitive binding to the enzyme by crystallographic precipitants such as citrate and sulfate. Here, a crystallographic technique termed precipitant-ligand exchange has been developed to exchange protein-bound precipitants with ligands of interest. Proof of concept for the exchange method was demonstrated using cytidine triphosphate (CTP), which adopted the same binding mechanism as that obtained with traditional crystal-soaking techniques. Precipitant-ligand exchange also yielded the previously intractable structure of MtDTBS in complex with ADP solved to 2.4 Å resolution. This result demonstrates the utility of precipitant-ligand exchange, which may be widely applicable to protein crystallography. |
Keywords: | Mycobacterium tuberculosis Carbon-Nitrogen Ligases Adenosine Diphosphate Cytidine Triphosphate Ligands Crystallography, X-Ray Binding Sites Binding, Competitive Protein Conformation Protein Binding |
Rights: | © International Union of Crystallography |
DOI: | 10.1107/S2059798318010136 |
Published version: | http://dx.doi.org/10.1107/s2059798318010136 |
Appears in Collections: | Aurora harvest 3 Earth and Environmental Sciences publications |
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