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- EMDB-18842: Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase (DXP... -

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Basic information

Entry
Database: EMDB / ID: EMD-18842
TitleCryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Plasmodium falciparum
Map data
Sample
  • Complex: Dimer of 1-deoxy-D-xylulose 5-phosphate synthase with Thiamin diphosphate bound.
    • Protein or peptide: 1-deoxy-D-xylulose-5-phosphate synthase
  • Ligand: MAGNESIUM ION
  • Ligand: THIAMINE DIPHOSPHATE
Keywords1-deoxy-D-xylulose 5-phosphate synthase / thiamin di-phosphate complex / transketolase / TRANSFERASE
Function / homology
Function and homology information


1-deoxy-D-xylulose-5-phosphate synthase / : / 1-deoxy-D-xylulose-5-phosphate synthase activity / thiamine biosynthetic process / terpenoid biosynthetic process / metal ion binding / membrane
Similarity search - Function
Deoxyxylulose-5-phosphate synthase / 1-deoxy-D-xylulose-5-phosphate synthase / Transketolase, C-terminal domain / Transketolase binding site / Transketolase signature 2. / Transketolase, C-terminal domain / Transketolase-like, pyrimidine-binding domain / Transketolase, pyrimidine binding domain / Transketolase, pyrimidine binding domain / Transketolase C-terminal/Pyruvate-ferredoxin oxidoreductase domain II / Thiamin diphosphate-binding fold
Similarity search - Domain/homology
1-deoxy-D-xylulose-5-phosphate synthase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.42 Å
AuthorsGawriljuk VO / Godoy AS / Oerlemans R / Groves MR
Funding supportEuropean Union, United Kingdom, 2 items
OrganizationGrant numberCountry
H2020 Marie Curie Actions of the European Commission860816European Union
Medical Research Council (MRC, United Kingdom)218785/Z/19/Z United Kingdom
CitationJournal: Nat Commun / Year: 2024
Title: Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase DXPS from Plasmodium falciparum reveals a distinct N-terminal domain.
Authors: Victor O Gawriljuk / Andre S Godoy / Rick Oerlemans / Luise A T Welker / Anna K H Hirsch / Matthew R Groves /
Abstract: 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 ...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.
History
DepositionNov 6, 2023-
Header (metadata) releaseJun 12, 2024-
Map releaseJun 12, 2024-
UpdateAug 14, 2024-
Current statusAug 14, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18842.png

Downloads & links

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Map

FileDownload / File: emd_18842.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 400 pix.
= 296. Å		0.74 Å/pix.
x 400 pix.
= 296. Å		0.74 Å/pix.
x 400 pix.
= 296. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.74 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.059852377 - 2.205356
Average (Standard dev.)0.0009618149 (±0.021254776)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 296.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18842_msk_1.map
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Additional map: #1

Fileemd_18842_additional_1.map
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Half map: #2

Fileemd_18842_half_map_1.map
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Half map: #1

Fileemd_18842_half_map_2.map
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Sample components

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Entire : Dimer of 1-deoxy-D-xylulose 5-phosphate synthase with Thiamin dip...

EntireName: Dimer of 1-deoxy-D-xylulose 5-phosphate synthase with Thiamin diphosphate bound.
Components
  • Complex: Dimer of 1-deoxy-D-xylulose 5-phosphate synthase with Thiamin diphosphate bound.
    • Protein or peptide: 1-deoxy-D-xylulose-5-phosphate synthase
  • Ligand: MAGNESIUM ION
  • Ligand: THIAMINE DIPHOSPHATE

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Supramolecule #1: Dimer of 1-deoxy-D-xylulose 5-phosphate synthase with Thiamin dip...

SupramoleculeName: Dimer of 1-deoxy-D-xylulose 5-phosphate synthase with Thiamin diphosphate bound.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)

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Macromolecule #1: 1-deoxy-D-xylulose-5-phosphate synthase

MacromoleculeName: 1-deoxy-D-xylulose-5-phosphate synthase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)
Molecular weightTheoretical: 105.953609 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSHHHHHH SSGLVPRGSH MYDIGKYFKQ INTFINIDEY KTIYGDEIYK EIYELYVERN IPEYYERKYF SEDIKKSVLF DIDKYNDVE FEKAIKEEFI NNGVYINNID NTYYKKENIL IMKKILHYFP LLKLINNPSD LKKLKKQYLP LLAHELKIFL F FIVNITGG ...String:
MGSSHHHHHH SSGLVPRGSH MYDIGKYFKQ INTFINIDEY KTIYGDEIYK EIYELYVERN IPEYYERKYF SEDIKKSVLF DIDKYNDVE FEKAIKEEFI NNGVYINNID NTYYKKENIL IMKKILHYFP LLKLINNPSD LKKLKKQYLP LLAHELKIFL F FIVNITGG HFSSVLSSLE IQLLLLYIFN QPYDNVIYDI GHQAYVHKIL TGRKLLFLSL RNKKGISGFL NIFESIYDKF GA GHSSTSL SAIQGYYEAE WQVKNKEKYG NGDIEISDNA NVTNNERIFQ KGIHNDNNIN NNINNNNYIN PSDVVGRENT NVP NVRNDN HNVDKVHIAI IGDGGLTGGM ALEALNYISF LNSKILIIYN DNGQVSLPTN AVSISGNRPI GSISDHLHYF VSNI EANAG DNKLSKNAKE NNIFENLNYD YIGVVNGNNT EELFKVLNNI KENKLKRATV LHVRTKKSND FINSKSPISI LHSIK KNEI FPFDTTILNG NIHKENKIEE EKNVSSSTKY DVNNKNNKNN DNSEIIKYED MFSKETFTDI YTNEMLKYLK KDRNII FLS PAMLGGSGLV KISERYPNNV YDVGIAEQHS VTFAAAMAMN KKLKIQLCIY STFLQRAYDQ IIHDLNLQNI PLKVIIG RS GLVGEDGATH QGIYDLSYLG TLNNAYIISP SNQVDLKRAL RFAYLDKDHS VYIRIPRMNI LSDKYMKGYL NIHMKNES K NIDVNVDIND DVDKYSEEYM DDDNFIKSFI GKSRIIKMDN ENNNTNEHYS SRGDTQTKKK KVCIFNMGSM LFNVINAIK EIEKEQYISH NYSFSIVDMI FLNPLDKNMI DHVIKQNKHQ YLITYEDNTI GGFSTHFNNY LIENNYITKH NLYVHNIYLS NEPIEHASF KDQQEVVKMD KCSLVNRIKN YLKNNPT

UniProtKB: 1-deoxy-D-xylulose-5-phosphate synthase

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Macromolecule #2: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #3: THIAMINE DIPHOSPHATE

MacromoleculeName: THIAMINE DIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: TPP
Molecular weightTheoretical: 425.314 Da
Chemical component information

ChemComp-TPP:
THIAMINE DIPHOSPHATE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.9 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 44.47 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionNumber classes used: 2 / Applied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.42 Å / Resolution method: FSC 0.143 CUT-OFF
Software: (Name: Coot (ver. 0.9.6), PHENIX (ver. 1.20.1-4487))
Number images used: 97205
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.1.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.1.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6694


Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
Output model

PDB-8r2h:
Cryo-EM structure of 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Plasmodium falciparum

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