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doi:10.22028/D291-39048
Titel: | First crystal structures of 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Mycobacterium tuberculosis indicate a distinct mechanism of intermediate stabilization |
VerfasserIn: | 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. |
Sprache: | Englisch |
Titel: | Scientific Reports |
Bandnummer: | 12 |
Heft: | 1 |
Verlag/Plattform: | Springer Nature |
Erscheinungsjahr: | 2022 |
Freie Schlagwörter: | Enzyme mechanisms Enzymes Molecular modelling Structural biology X-ray crystallography |
DDC-Sachgruppe: | 500 Naturwissenschaften |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | The 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 frst 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 frst DXPS structures of a pathogen, namely M. tuberculosis (MtDXPS). The main diference 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 identifed in the enamine structure, using a diferent 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 specifc for MtDXPS through structure-based drug design. |
DOI der Erstveröffentlichung: | 10.1038/s41598-022-11205-9 |
URL der Erstveröffentlichung: | https://www.nature.com/articles/s41598-022-11205-9 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-390486 hdl:20.500.11880/35216 http://dx.doi.org/10.22028/D291-39048 |
ISSN: | 2045-2322 |
Datum des Eintrags: | 16-Feb-2023 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary Information |
In Beziehung stehendes Objekt: | https://static-content.springer.com/esm/art%3A10.1038%2Fs41598-022-11205-9/MediaObjects/41598_2022_11205_MOESM1_ESM.docx |
Fakultät: | NT - Naturwissenschaftlich- Technische Fakultät |
Fachrichtung: | NT - Pharmazie |
Professur: | NT - Prof. Dr. Anna Hirsch |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
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s41598-022-11205-9.pdf | 2,64 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons