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- PDB-9cca: Cryo-EM structure of a designed pyridoxal phosphate (PLP) synthas... -

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Basic information

Entry
Database: PDB / ID: 9cca
TitleCryo-EM structure of a designed pyridoxal phosphate (PLP) synthase fused to a designed circumsporozoite protein antigen from Plasmodium falciparum (CSP-P1-CSP and CSP-P2-CSP)
Components
  • Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
  • Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
KeywordsBIOSYNTHETIC PROTEIN / synthase / complex
Function / homology
Function and homology information


vitamin B6 biosynthetic process / amine-lyase activity / pyridoxine metabolic process / glutaminase complex / pyridoxal 5'-phosphate synthase (glutamine hydrolysing) / pyridoxal 5'-phosphate synthase (glutamine hydrolysing) activity / response to singlet oxygen / pyridoxal phosphate biosynthetic process / pyridoxine biosynthetic process / host cell surface binding ...vitamin B6 biosynthetic process / amine-lyase activity / pyridoxine metabolic process / glutaminase complex / pyridoxal 5'-phosphate synthase (glutamine hydrolysing) / pyridoxal 5'-phosphate synthase (glutamine hydrolysing) activity / response to singlet oxygen / pyridoxal phosphate biosynthetic process / pyridoxine biosynthetic process / host cell surface binding / glutaminase / symbiont entry into host / entry into host cell by a symbiont-containing vacuole / glutaminase activity / heparan sulfate proteoglycan binding / amino acid metabolic process / catalytic activity / side of membrane / cell surface / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Pyridoxal 5'-phosphate synthase subunit PdxT/SNO / PdxT/SNO family, conserved site / SNO glutamine amidotransferase family / PdxT/SNO family family signature. / PdxT/SNO family profile. / Pyridoxal 5'-phosphate synthase subunit PdxS/SNZ / PdxS/SNZ N-terminal domain / SOR/SNZ family / PdxS/SNZ family signature. / PdxS/SNZ family profile. ...Pyridoxal 5'-phosphate synthase subunit PdxT/SNO / PdxT/SNO family, conserved site / SNO glutamine amidotransferase family / PdxT/SNO family family signature. / PdxT/SNO family profile. / Pyridoxal 5'-phosphate synthase subunit PdxS/SNZ / PdxS/SNZ N-terminal domain / SOR/SNZ family / PdxS/SNZ family signature. / PdxS/SNZ family profile. / : / Plasmodium circumsporozoite protein / Thrombospondin type 1 domain / Thrombospondin type-1 (TSP1) repeat superfamily / Thrombospondin type-1 (TSP1) repeat profile. / Thrombospondin type 1 repeats / Thrombospondin type-1 (TSP1) repeat / Ribulose-phosphate binding barrel / Class I glutamine amidotransferase-like / Aldolase-type TIM barrel
Similarity search - Domain/homology
Pyridoxal 5'-phosphate synthase subunit Pdx1 / Circumsporozoite protein / Pyridoxal 5'-phosphate synthase subunit PDX2
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsShi, D. / Ma, R. / Tang, W.K. / Tolia, N.H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)1ZIAAI001253 United States
CitationJournal: Nat Microbiol / Year: 2025
Title: A Plasmodium-derived nanoparticle vaccine elicits sterile protection against malaria in mice.
Authors: Dashuang Shi / Rui Ma / Richi Gupta / Thayne H Dickey / Palak N Patel / Nichole D Salinas / Wai Kwan Tang / Alaysies Queen / Myesha Singleton / Nida Delbe / Solomon Conteh / Lynn E Lambert / ...Authors: Dashuang Shi / Rui Ma / Richi Gupta / Thayne H Dickey / Palak N Patel / Nichole D Salinas / Wai Kwan Tang / Alaysies Queen / Myesha Singleton / Nida Delbe / Solomon Conteh / Lynn E Lambert / Patrick E Duffy / Niraj H Tolia /
Abstract: Protein nanoparticles in infectious disease vaccines enable protection through the periodic arrangement of antigens on their surface. These nanoparticles arise from organisms unrelated to the target ...Protein nanoparticles in infectious disease vaccines enable protection through the periodic arrangement of antigens on their surface. These nanoparticles arise from organisms unrelated to the target disease, limiting their role as presentation platforms. Nanoparticles may also be compromised by pre-existing immunity to the nanoparticle carrier and may induce autoimmunity if conserved epitopes exist. Here we developed a potent multivalent malaria vaccine using an engineered Plasmodium falciparum pyridoxal 5'-phosphate (PLP) synthase as a nanoparticle that presents a designed P. falciparum circumsporozoite protein (CSP) and the Plasmodium vivax cell-transversal protein for ookinetes and sporozoites (CelTOS). These engineered vaccines elicited high titres of anti-CSP and anti-CelTOS antibodies, and three doses provided complete sterile protection against malaria in a mouse model. Cryogenic electron microscopy resolved a 2.95-Å resolution structure of the PLP nanoparticle including amino acid changes engineered to stabilize the nanoparticle. PLP synthase has no identifiable human ortholog limiting its propensity for autoimmunity or pre-existing immunity, and the engineered nanoparticles possess desirable manufacturing characteristics. These studies established an effective nanoparticle platform for malaria and infectious disease vaccines.
History
DepositionJun 21, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 31, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 31, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 31, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Dec 31, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 31, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 31, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 31, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
B: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
C: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
D: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
E: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
F: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
G: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
H: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
I: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
J: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
K: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
L: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
M: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
N: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
O: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
P: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
Q: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
R: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1
S: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
T: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
U: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
V: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
W: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2
X: Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2


Theoretical massNumber of molelcules
Total (without water)1,299,12824
Polymers1,299,12824
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit Pdx1


Mass: 58417.055 Da / Num. of mol.: 12
Mutation: K198R,K289C,S293C in Pdx1 (Uniprot numbering: K83R,K174C,S178C)
Source method: isolated from a genetically manipulated source
Details: Pdx1 between duplicated portions of CSP (residues 101 to 114, 131 to 150, 310 to 383), so that it is CSP-Pdx1-CSP
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CSP, PF3D7_0304600, pdx1, PFF1025c / Production host: Escherichia coli (E. coli)
References: UniProt: Q7K740, UniProt: C6KT50, pyridoxal 5'-phosphate synthase (glutamine hydrolysing)
#2: Protein
Circumsporozoite protein,Pyridoxal 5'-phosphate synthase subunit PDX2


Mass: 49843.617 Da / Num. of mol.: 12
Mutation: N179Q,N242Q,H310N in Pdx2 (Uniprot numbering: N65Q,N128Q,H196N)
Source method: isolated from a genetically manipulated source
Details: Pdx2 between duplicated portions of CSP (residues 101 to 114, 131 to 150, 310 to 383), so that it is CSP-Pdx2-CSP
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CSP, PF3D7_0304600, PDX2, PF11_0169, PF3D7_1116200 / Production host: Escherichia coli (E. coli)
References: UniProt: Q7K740, UniProt: Q8IIK4, pyridoxal 5'-phosphate synthase (glutamine hydrolysing), glutaminase
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Complex of CSP-P1-CSP and CSP-P2-CSPCOMPLEXall0RECOMBINANT
2CSP-P1-CSPCOMPLEX#11RECOMBINANT
3CSP-P2-CSPCOMPLEX#21RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Plasmodium falciparum (malaria parasite P. falciparum)5833
33Plasmodium falciparum (malaria parasite P. falciparum)5833
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Escherichia coli (E. coli)562
33Escherichia coli (E. coli)562
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 53.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286 / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 251050 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL / Target criteria: Cross-correlation coeffcient
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeSource nameType
14ADT

4adt

14ADTPDBexperimental model
22ABW

2abw

12ABWPDBexperimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 61.01 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.004241301
ELECTRON MICROSCOPYf_angle_d0.481855703
ELECTRON MICROSCOPYf_chiral_restr0.04376571
ELECTRON MICROSCOPYf_plane_restr0.00357051
ELECTRON MICROSCOPYf_dihedral_angle_d4.0175505

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