Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase DXPS from Plasmodium falciparum reveals a distinct N-terminal domain.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 Aug 2024
05 Aug 2024
Historique:
received:
18
12
2023
accepted:
17
07
2024
medline:
6
8
2024
pubmed:
6
8
2024
entrez:
5
8
2024
Statut:
epublish
Résumé
Plasmodium falciparum is the main causative agent of malaria, a deadly disease that mainly affects children under five years old. Artemisinin-based combination therapies have been pivotal in controlling the disease, but resistance has arisen in various regions, increasing the risk of treatment failure. The non-mevalonate pathway is essential for the isoprenoid synthesis in Plasmodium and provides several under-explored targets to be used in the discovery of new antimalarials. 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) is the first and rate-limiting enzyme of the pathway. Despite its importance, there are no structures available for any Plasmodium spp., due to the complex sequence which contains large regions of high disorder, making crystallisation a difficult task. In this manuscript, we use cryo-electron microscopy to solve the P. falciparum DXPS structure at a final resolution of 2.42 Å. Overall, the structure resembles other DXPS enzymes but includes a distinct N-terminal domain exclusive to the Plasmodium genus. Mutational studies show that destabilization of the cap domain interface negatively impacts protein stability and activity. Additionally, a density for the co-factor thiamine diphosphate is found in the active site. Our work highlights the potential of cryo-EM to obtain structures of P. falciparum proteins that are unfeasible by means of crystallography.
Identifiants
pubmed: 39103329
doi: 10.1038/s41467-024-50671-9
pii: 10.1038/s41467-024-50671-9
doi:
Substances chimiques
deoxyxylulose-5-phosphate synthase
EC 2.2.1.-
Pentosyltransferases
EC 2.4.2.-
Protozoan Proteins
0
Transferases
EC 2.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6642Subventions
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions)
ID : 860816
Informations de copyright
© 2024. The Author(s).
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