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Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase DXPS from Plasmodium falciparum reveals a distinct N-terminal domain
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Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase DXPS from Plasmodium falciparum reveals a distinct N-terminal domain
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Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase DXPS from Plasmodium falciparum reveals a distinct N-terminal domain
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Journal Article
Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase DXPS from Plasmodium falciparum reveals a distinct N-terminal domain
2024
Overview
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.
DXPS is an important enzyme for isoprenoid synthesis in
Plasmodium falciparum
. Here, authors elucidate the cryo-EM structure of
Pf
DXPS showing an N-terminal domain only present in this genus. Mutation studies show its importance in DXPS stability and activity.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Enzymes
/ Humanities and Social Sciences
/ Malaria
/ Pentosyltransferases - chemistry
/ Pentosyltransferases - genetics
/ Pentosyltransferases - metabolism
/ Pentosyltransferases - ultrastructure
/ Plasmodium falciparum - enzymology
/ Plasmodium falciparum - genetics
/ Proteins
/ Protozoan Proteins - chemistry
/ Protozoan Proteins - genetics
/ Protozoan Proteins - metabolism
/ Protozoan Proteins - ultrastructure
/ Science
/ Thiamine
/ Xylulose
