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- PDB-8cdd: PfRH5-PfCyRPA-PfRIPR complex from Plasmodium falciparum bound to ... -

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Basic information

Entry
Database: PDB / ID: 8cdd
TitlePfRH5-PfCyRPA-PfRIPR complex from Plasmodium falciparum bound to antibody Cy.003
Components
  • Cy.003 heavy chain
  • Cy.003 light chain
  • Cysteine-rich protective antigen
  • Reticulocyte-binding protein homolog 5
  • Rh5-interacting protein
KeywordsCELL ADHESION / Plasmodium falciparum / erythrocyte-invasion / PfRCR / blood stage malaria vaccine
Function / homology
Function and homology information


rhoptry lumen / rhoptry / microneme lumen / microneme / symbiont entry into host / host cell membrane / bicellular tight junction / apical part of cell / heparin binding / cytoplasmic vesicle ...rhoptry lumen / rhoptry / microneme lumen / microneme / symbiont entry into host / host cell membrane / bicellular tight junction / apical part of cell / heparin binding / cytoplasmic vesicle / host extracellular space / host cell surface receptor binding / host cell plasma membrane / protein-containing complex / extracellular region / membrane / plasma membrane
Similarity search - Function
Rh5 coiled-coil domain / Rh5 coiled-coil domain / Cysteine-rich protective antigen 6 bladed domain / Cysteine-Rich Protective Antigen 6 bladed domain / Epidermal growth factor-like domain. / EGF-like domain signature 2. / EGF-like domain
Similarity search - Domain/homology
Rh5-interacting protein / Reticulocyte-binding protein homolog 5 / Cysteine-rich protective antigen
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
Gallus gallus (chicken)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsFarrell, B. / Higgins, M.K.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust220797/Z/20/Z United Kingdom
CitationJournal: Nature / Year: 2024
Title: The PfRCR complex bridges malaria parasite and erythrocyte during invasion.
Authors: Brendan Farrell / Nawsad Alam / Melissa N Hart / Abhishek Jamwal / Robert J Ragotte / Hannah Walters-Morgan / Simon J Draper / Ellen Knuepfer / Matthew K Higgins /
Abstract: The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The PfPCRCR complex, containing PfRH5 (refs. ), PfCyRPA, PfRIPR, ...The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The PfPCRCR complex, containing PfRH5 (refs. ), PfCyRPA, PfRIPR, PfCSS and PfPTRAMP, is essential for erythrocyte invasion by the deadliest human malaria parasite, Plasmodium falciparum. Invasion can be prevented by antibodies or nanobodies against each of these conserved proteins, making them the leading blood-stage malaria vaccine candidates. However, little is known about how PfPCRCR functions during invasion. Here we present the structure of the PfRCR complex, containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. We test the hypothesis that PfRH5 opens to insert into the membrane, instead showing that a rigid, disulfide-locked PfRH5 can mediate efficient erythrocyte invasion. We show, through modelling and an erythrocyte-binding assay, that PfCyRPA-binding antibodies neutralize invasion through a steric mechanism. We determine the structure of PfRIPR, showing that it consists of an ordered, multidomain core flexibly linked to an elongated tail. We also show that the elongated tail of PfRIPR, which is the target of growth-neutralizing antibodies, binds to the PfCSS-PfPTRAMP complex on the parasite membrane. A modular PfRIPR is therefore linked to the merozoite membrane through an elongated tail, and its structured core presents PfCyRPA and PfRH5 to interact with erythrocyte receptors. This provides fresh insight into the molecular mechanism of erythrocyte invasion and opens the way to new approaches in rational vaccine design.
History
DepositionJan 30, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 25, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jan 3, 2024Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jan 31, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.4Feb 7, 2024Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Rh5-interacting protein
B: Cysteine-rich protective antigen
C: Reticulocyte-binding protein homolog 5
D: Cy.003 light chain
E: Cy.003 heavy chain


Theoretical massNumber of molelcules
Total (without water)270,0625
Polymers270,0625
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10250 Å2
ΔGint-42 kcal/mol
Surface area74680 Å2

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Components

#1: Protein Rh5-interacting protein / PfRipr


Mass: 124275.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: RIPR, PFC1045C, PF3D7_0323400 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: O97302
#2: Protein Cysteine-rich protective antigen / Inactive sialidase CyRPA / PfCyRPA


Mass: 40184.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: CyRPA, pfd1130w, PF3D7_0423800 / Production host: Homo sapiens (human) / References: UniProt: Q8IFM8
#3: Protein Reticulocyte-binding protein homolog 5 / PfRH5


Mass: 60157.004 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: RH5, PFD1145c, PF3D7_0424100 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: Q8IFM5
#4: Protein Cy.003 light chain


Mass: 22083.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Production host: Homo sapiens (human)
#5: Antibody Cy.003 heavy chain


Mass: 23362.984 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Production host: Homo sapiens (human)

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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

ComponentName: PfRH5-PfCyRPA-PfRIPR complex bound to Fab fragment from antibody Cy.003
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 48.97 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 500277 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00313419
ELECTRON MICROSCOPYf_angle_d0.63918118
ELECTRON MICROSCOPYf_dihedral_angle_d4.4341766
ELECTRON MICROSCOPYf_chiral_restr0.0441972
ELECTRON MICROSCOPYf_plane_restr0.0032323

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