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- EMDB-16569: PfRH5-PfCyRPA-PfRIPR complex from Plasmodium falciparum bound to ... -

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Basic information

Entry
Database: EMDB / ID: EMD-16569
TitlePfRH5-PfCyRPA-PfRIPR complex from Plasmodium falciparum bound to antibody Cy.003
Map datacomposite map
Sample
  • Complex: PfRH5-PfCyRPA-PfRIPR complex bound to Fab fragment from antibody Cy.003
    • Protein or peptide: Rh5-interacting protein
    • Protein or peptide: Cysteine-rich protective antigen
    • Protein or peptide: Reticulocyte-binding protein homolog 5
    • Protein or peptide: Cy.003 light chain
    • Protein or peptide: Cy.003 heavy chain
KeywordsPlasmodium falciparum / erythrocyte-invasion / PfRCR / blood stage malaria vaccine / CELL ADHESION
Function / homology
Function and homology information


rhoptry lumen / microneme lumen / rhoptry / microneme / symbiont entry into host / host cell membrane / bicellular tight junction / apical part of cell / heparin binding / cytoplasmic vesicle ...rhoptry lumen / microneme lumen / rhoptry / 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
: / Cysteine-rich protective antigen 6 bladed domain / Cysteine-Rich Protective Antigen 6 bladed domain / Rh5 coiled-coil domain / Rh5 coiled-coil 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsFarrell B / Higgins MK
Funding support United Kingdom, 1 items
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, 2023-
Header (metadata) releaseOct 25, 2023-
Map releaseOct 25, 2023-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16569.png

Downloads & links

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Map

FileDownload / File: emd_16569.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcomposite map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 416 pix.
= 346.112 Å		0.83 Å/pix.
x 416 pix.
= 346.112 Å		0.83 Å/pix.
x 416 pix.
= 346.112 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 8.0
Minimum - Maximum-44.522624999999998 - 78.649604999999994
Average (Standard dev.)0.012745163 (±1.1968918)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 346.112 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: composite map after DeepEMhancer

Fileemd_16569_additional_1.map
Annotationcomposite map after DeepEMhancer
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : PfRH5-PfCyRPA-PfRIPR complex bound to Fab fragment from antibody ...

EntireName: PfRH5-PfCyRPA-PfRIPR complex bound to Fab fragment from antibody Cy.003
Components
  • Complex: PfRH5-PfCyRPA-PfRIPR complex bound to Fab fragment from antibody Cy.003
    • Protein or peptide: Rh5-interacting protein
    • Protein or peptide: Cysteine-rich protective antigen
    • Protein or peptide: Reticulocyte-binding protein homolog 5
    • Protein or peptide: Cy.003 light chain
    • Protein or peptide: Cy.003 heavy chain

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Supramolecule #1: PfRH5-PfCyRPA-PfRIPR complex bound to Fab fragment from antibody ...

SupramoleculeName: PfRH5-PfCyRPA-PfRIPR complex bound to Fab fragment from antibody Cy.003
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)

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Macromolecule #1: Rh5-interacting protein

MacromoleculeName: Rh5-interacting protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Molecular weightTheoretical: 124.275094 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: DLIEGIFYEK NEIDKLTFSL DHRVRDNLKT DLILNNNGEN DYAYLNKYVY TILNRDSTEK IKTFFSHNKD MKSCDYFISK EYQSSDKTN QICYKKTFCG VVIPNSEEIK TNKITNDKLY CAHFQSTHII IYYISQPLLL EPHVVYEETF FEKGKNDQIN C QGMYISLR ...String:
DLIEGIFYEK NEIDKLTFSL DHRVRDNLKT DLILNNNGEN DYAYLNKYVY TILNRDSTEK IKTFFSHNKD MKSCDYFISK EYQSSDKTN QICYKKTFCG VVIPNSEEIK TNKITNDKLY CAHFQSTHII IYYISQPLLL EPHVVYEETF FEKGKNDQIN C QGMYISLR SVHVHTHNAI LQQETLTYIK NLCDGKNNCK FDFDSIKYEQ KSLTHYLFFI NIQYQCISPL NLQENEMCDV YN DDTHKAT CKYGFNKIEL LKNVCEENYR CTQDICSVNQ FCDGENETCT CKTSLLPSAK NNCEYNDLCT VLNCPEQSTC EQI GNGKKA ECKCENGKYY HNNKCYTKND LELAIKIEPH KKEKFYKNNL YQGKALKPEY IFMQCENGFS IEVINAYVSC YRVS FNLNK LKYVTESLKK MCDGKTKCAY GNTIDPIDDL NHHNICNNFN TIFKYDYLCV FNNQQITSDK NSHLHSNIPS LYQSS ILPD IQKSKFHLIS RNSRTNQYPH NQISMLEIQN EISSHNSNQF STDPHTNSNN INNMNIKKVE IFRSRFSSKL QCQGGK INI DKAILKGGEG CNDLLLTNSL KSYCNDLSEC DIGLIYHFDT YCINDQYLFV SYSCSNLCNK CHQQSTCYGN RFNYDCF CD NPYISKYGNK LCERPNDCES VLCSQNQVCQ ILPNDKLICQ CEEGYKNVKG KCVPDNKCDL SCPSNKVCVI ENGKQTCK C SERFVLENGV CICANDYKME DGINCIAKNK CKRKEYENIC TNPNEMCAYN EETDIVKCEC KEHYYRSSRG ECILNDYCK DINCKENEEC SIVNFKPECV CKENLKKNNK GECIYENSCL INEGNCPKDS KCIYREYKPH ECVCNKQGHV AVNGKCVLED KCVHNKKCS ENSICVNVMN KEPICVCTYN YYKKDGVCLI QNPCLKDNGG CSRNSECTFK YSKIQCTCKE NYKNKDDSCV P NTNEYDES FTFQYNDDAS IILGACGMIE FSYIYNQIIW KIQNSKESYV FYYDYPTAGN IEVQIKNEIF HTIIYLKKKI GN SVIYDDF QVDHQTCIYE NVFYYSNQNE PEA

UniProtKB: Rh5-interacting protein

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Macromolecule #2: Cysteine-rich protective antigen

MacromoleculeName: Cysteine-rich protective antigen / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Molecular weightTheoretical: 40.184039 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DSRHVFIRTE LSFIKNNVPC IRDMFFIYKR ELYNICLDDL KGEEDETHIY VQKKVKDSWI TLNDLFKETD LTGRPHIFAY VDVEEIIIL LCEDEEFSNR KKDMTCHRFY SNDGKEYNNA EITISDYILK DKLLSSYVSL PLKIENREYF LICGVSPYKF K DDNKKDDI ...String:
DSRHVFIRTE LSFIKNNVPC IRDMFFIYKR ELYNICLDDL KGEEDETHIY VQKKVKDSWI TLNDLFKETD LTGRPHIFAY VDVEEIIIL LCEDEEFSNR KKDMTCHRFY SNDGKEYNNA EITISDYILK DKLLSSYVSL PLKIENREYF LICGVSPYKF K DDNKKDDI LCMASHDKGE TWGTKIVIKY DNYKLGVQYF FLRPYISKND LSFHFYVGDN INNVKNVNFI ECTHEKDLEF VC SNRDFLK DNKVLQDVST LNDEYIVSYG NDNNFAECYI FFNNENSILI KPEKYGNTAA GCYGGTFVKI DENRALFIYS SSQ GIYNIH TIYYANYEGG GGSEPEA

UniProtKB: Cysteine-rich protective antigen

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Macromolecule #3: Reticulocyte-binding protein homolog 5

MacromoleculeName: Reticulocyte-binding protein homolog 5 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Molecular weightTheoretical: 60.157004 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: FENAIKKTKN QENNLTLLPI KSTEEEKDDI KNGKDIKKEI DNDKENIKTN NAKDHSTYIK SYLNTNVNDG LKYLFIPSHN SFIKKYSVF NQINDGMLLN EKNDVKNNED YKNVDYKNVN FLQYHFKELS NYNIANSIDI LQEKEGHLDF VIIPHYTFLD Y YKHLSYNS ...String:
FENAIKKTKN QENNLTLLPI KSTEEEKDDI KNGKDIKKEI DNDKENIKTN NAKDHSTYIK SYLNTNVNDG LKYLFIPSHN SFIKKYSVF NQINDGMLLN EKNDVKNNED YKNVDYKNVN FLQYHFKELS NYNIANSIDI LQEKEGHLDF VIIPHYTFLD Y YKHLSYNS IYHKSSTYGK YIAVDAFIKK INEAYDKVKS KCNDIKNDLI ATIKKLEHPY DINNKNDDSY RYDISEEIDD KS EETDDET EEVEDSIQDT DSNHTPSNKK KNDLMNRAFK KMMDEYNTKK KKLIKCIKNH ENDFNKICMD MKNYGTNLFE QLS CYNNNF CNTNGIRYHY DEYIHKLILS VKSKNLNKDL SDMTNILQQS ELLLTNLNKK MGSYIYIDTI KFIHKEMKHI FNRI EYHTK IINDKTKIIQ DKIKLNIWRT FQKDELLKRI LDMSNEYSLF ITSDHLRQML YNTFYSKEKH LNNIFHHLIY VLQMK FNDV PIKMEYFQTY KKNKPLTQ

UniProtKB: Reticulocyte-binding protein homolog 5

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Macromolecule #4: Cy.003 light chain

MacromoleculeName: Cy.003 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Gallus gallus (chicken)
Molecular weightTheoretical: 22.083281 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ALTQPSSVSA NPGETVKITC SGGSSSYYGW YQQKSPGSAP VTLIYNNQKR PSDIPSRFSG SKSGSTGTLT ITGVQAEDEA VYFCGSRDN SGGIFGAGTT LTVLRTVAAP SVFIFPPSDE QLKSGTASVV CLLNNFYPRE AKVQWKVDNA LQSGNSQESV T EQDSKDST ...String:
ALTQPSSVSA NPGETVKITC SGGSSSYYGW YQQKSPGSAP VTLIYNNQKR PSDIPSRFSG SKSGSTGTLT ITGVQAEDEA VYFCGSRDN SGGIFGAGTT LTVLRTVAAP SVFIFPPSDE QLKSGTASVV CLLNNFYPRE AKVQWKVDNA LQSGNSQESV T EQDSKDST YSLSSTLTLS KADYEKHKVY ACEVTHQGLS SPVTKSFNR

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Macromolecule #5: Cy.003 heavy chain

MacromoleculeName: Cy.003 heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Gallus gallus (chicken)
Molecular weightTheoretical: 23.362984 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AVTLDESGGG LQTPGGALSL VCKGSGFFSF SSYTMQWVRQ APGKGLEWVA SISSGGGTNY GAAVKGRATI SRDNGQSTLR LQLNNLRAE DTGTYYCAKH GVNGCDWSYS VGCVDAWGHG TEVIVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF P EPVTVSWN ...String:
AVTLDESGGG LQTPGGALSL VCKGSGFFSF SSYTMQWVRQ APGKGLEWVA SISSGGGTNY GAAVKGRATI SRDNGQSTLR LQLNNLRAE DTGTYYCAKH GVNGCDWSYS VGCVDAWGHG TEVIVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF P EPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKKVEP

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 48.97 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 500277
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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