Author:
Gierse Robin M.,Oerlemans Rick,Reddem Eswar R.,Gawriljuk Victor O.,Alhayek Alaa,Baitinger Dominik,Jakobi Harald,Laber Bernd,Lange Gudrun,Hirsch Anna K. H.,Groves Matthew R.
Abstract
AbstractThe development of drug resistance by Mycobacterium tuberculosis and other pathogenic bacteria emphasizes the need for new antibiotics. Unlike animals, most bacteria synthesize isoprenoid precursors through the MEP pathway. 1-Deoxy-d-xylulose 5-phosphate synthase (DXPS) catalyzes the first reaction of the MEP pathway and is an attractive target for the development of new antibiotics. We report here the successful use of a loop truncation to crystallize and solve the first DXPS structures of a pathogen, namely M. tuberculosis (MtDXPS). The main difference found to other DXPS structures is in the active site where a highly coordinated water was found, showing a new mechanism for the enamine-intermediate stabilization. Unlike other DXPS structures, a “fork-like” motif could be identified in the enamine structure, using a different residue for the interaction with the cofactor, potentially leading to a decrease in the stability of the intermediate. In addition, electron density suggesting a phosphate group could be found close to the active site, provides new evidence for the D-GAP binding site. These results provide the opportunity to improve or develop new inhibitors specific for MtDXPS through structure-based drug design.
Funder
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
H2020 Marie Skłodowska-Curie Actions
Publisher
Springer Science and Business Media LLC
Cited by
6 articles.
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