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- EMDB-44539: Cryo-EM structure of human monoclonal antibody C74 targeting PFD1... -

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Basic information

Entry
Database: EMDB / ID: EMD-44539
TitleCryo-EM structure of human monoclonal antibody C74 targeting PFD1235w (CIDRa1.6) PfEMP1
Map data
Sample
  • Cell: Complex of human monoclonal C74 with PfEMP1 PFD1235w N-terminal domain complex
    • Protein or peptide: C74 heavy chain
    • Protein or peptide: C74 kappa chain
    • Protein or peptide: Erythrocyte membrane protein 1, PfEMP1
KeywordsAntibody / Plasmodium / Monoclonal / Neutralizing / IMMUNE SYSTEM
Function / homology
Function and homology information


symbiont-mediated perturbation of host erythrocyte aggregation / infected host cell surface knob / antigenic variation / adhesion of symbiont to microvasculature / cell adhesion molecule binding / cell-cell adhesion / host cell surface receptor binding / host cell plasma membrane / membrane
Similarity search - Function
: / PfEMP1 protein, CIDRalpha1 domain / Plasmodium falciparum erythrocyte membrane protein-1, N-terminal segment / N-terminal segments of PfEMP1 / : / Cysteine-rich interdomain region 1 gamma / Cysteine-Rich Interdomain Region 1 gamma / Duffy-binding-like domain, C-terminal subdomain / Duffy-binding-like domain / PFEMP1 DBL domain ...: / PfEMP1 protein, CIDRalpha1 domain / Plasmodium falciparum erythrocyte membrane protein-1, N-terminal segment / N-terminal segments of PfEMP1 / : / Cysteine-rich interdomain region 1 gamma / Cysteine-Rich Interdomain Region 1 gamma / Duffy-binding-like domain, C-terminal subdomain / Duffy-binding-like domain / PFEMP1 DBL domain / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment superfamily / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment / acidic terminal segments, variant surface antigen of PfEMP1 / Duffy-antigen binding / Duffy-antigen binding superfamily / Duffy binding domain
Similarity search - Domain/homology
Erythrocyte membrane protein 1, PfEMP1
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsRaghavan SSR / Ward AB
Funding support United States, Denmark, 2 items
OrganizationGrant numberCountry
Bill & Melinda Gates Foundation United States
Lundbeckfonden Denmark
CitationJournal: Nature / Year: 2024
Title: Broadly inhibitory antibodies to severe malaria virulence proteins.
Authors: Raphael A Reyes / Sai Sundar Rajan Raghavan / Nicholas K Hurlburt / Viola Introini / Sebastiaan Bol / Ikhlaq Hussain Kana / Rasmus W Jensen / Elizabeth Martinez-Scholze / María Gestal-Mato ...Authors: Raphael A Reyes / Sai Sundar Rajan Raghavan / Nicholas K Hurlburt / Viola Introini / Sebastiaan Bol / Ikhlaq Hussain Kana / Rasmus W Jensen / Elizabeth Martinez-Scholze / María Gestal-Mato / Borja López-Gutiérrez / Silvia Sanz / Cristina Bancells / Monica Lisa Fernández-Quintero / Johannes R Loeffler / James Alexander Ferguson / Wen-Hsin Lee / Greg Michael Martin / Thor G Theander / John P A Lusingu / Daniel T R Minja / Isaac Ssewanyana / Margaret E Feeney / Bryan Greenhouse / Andrew B Ward / Maria Bernabeu / Marie Pancera / Louise Turner / Evelien M Bunnik / Thomas Lavstsen /
Abstract: Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) ...Malaria pathology is driven by the accumulation of Plasmodium falciparum-infected erythrocytes in microvessels. This process is mediated by the polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins of the parasite. A subset of PfEMP1 variants that bind to human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here we describe two broadly reactive and inhibitory human monoclonal antibodies to CIDRα1. The antibodies isolated from two different individuals exhibited similar and consistent EPCR-binding inhibition of diverse CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins, as well as parasite sequestration in bioengineered 3D human brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with three different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies are likely to represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.
History
DepositionApr 19, 2024-
Header (metadata) releaseOct 2, 2024-
Map releaseOct 2, 2024-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44539.png

Downloads & links

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Map

FileDownload / File: emd_44539.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 360 pix.
= 261. Å		0.73 Å/pix.
x 360 pix.
= 261. Å		0.73 Å/pix.
x 360 pix.
= 261. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.725 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.085
Minimum - Maximum-0.43072158 - 0.6839186
Average (Standard dev.)0.000057604062 (±0.008648803)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 261.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_44539_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

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Half map: #1

Fileemd_44539_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Complex of human monoclonal C74 with PfEMP1 PFD1235w N-terminal d...

EntireName: Complex of human monoclonal C74 with PfEMP1 PFD1235w N-terminal domain complex
Components
  • Cell: Complex of human monoclonal C74 with PfEMP1 PFD1235w N-terminal domain complex
    • Protein or peptide: C74 heavy chain
    • Protein or peptide: C74 kappa chain
    • Protein or peptide: Erythrocyte membrane protein 1, PfEMP1

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Supramolecule #1: Complex of human monoclonal C74 with PfEMP1 PFD1235w N-terminal d...

SupramoleculeName: Complex of human monoclonal C74 with PfEMP1 PFD1235w N-terminal domain complex
type: cell / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)

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Macromolecule #1: C74 heavy chain

MacromoleculeName: C74 heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.441013 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
EVQLVQSGGA LVRPGGSLRL SCAASGFDFS DFEMNWVRQA PGKGLEWISY ISKISAASFY ADSVEGRFTI SRDNTKNLLW LEMTSLRDE DTAVYYCARD LPGYLERVFD LWGQGTLVSV SS

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Macromolecule #2: C74 kappa chain

MacromoleculeName: C74 kappa chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.178488 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
EIVLTQSPAT LSLSPGEDAT LSCRASQSVG SALAWYQHRP GQSPRLLIYD ASTRATGIPA RFSGSGSGTE FTLTVSSLTS EDFAVYYCQ EYKNSVPPTW TFGQGTKVEI KRTV

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Macromolecule #3: Erythrocyte membrane protein 1, PfEMP1

MacromoleculeName: Erythrocyte membrane protein 1, PfEMP1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Molecular weightTheoretical: 85.069266 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGNASSSEGE AKTPSLTESH NSARNILEGY AESIKEQASK DAKIHGHHLK GDLAKAVFRH PFSAYRPNYG NPCELDYRFH TNVWHRNAE DRNPCLFSRA KRFSNEGEAE CNGGIITGNK GECGACAPYR RRHICDYNLH HINENNIRNT HDLLGNLLVM A RSEGESIV ...String:
MGNASSSEGE AKTPSLTESH NSARNILEGY AESIKEQASK DAKIHGHHLK GDLAKAVFRH PFSAYRPNYG NPCELDYRFH TNVWHRNAE DRNPCLFSRA KRFSNEGEAE CNGGIITGNK GECGACAPYR RRHICDYNLH HINENNIRNT HDLLGNLLVM A RSEGESIV KSHEYTGYGI YKSGICTSLA RSFADIGDII RGKDLYRRDS RTDKLEENLR KIFANIYKEL KNGKKWAEAK EY YQDDGTG NYYKLREAWW ALNRKDVWKA LTCSAPRDAQ YFIKSSVRDQ TFSNDYCGHG EHEVLTNLDY VPQFLRWFEE WAE EFCRIK KIKLGKVKEA CRDDSKKLYC SHNGYDCTKT IRNKDILSDN PKCTGCSVKC KVYELWLRNQ RNEFEKQKKK YYKE IQTYT SKDAKTDSNI NNEYYKEFYD KLKNEGYETL NKFIKLLNEG RYCKEKISGE RNIDFTMTGD KDAFYRSDYC QICPE CGVQ CSGTTCTPKK VIHPNCKDKE TYEPGDAKTT DITVLYSGDE EGDIAQKLQD FCNDKNKEND ENYEKWQCYY KSSEIN KCQ MTPSSHKVPK HGYIMSFYAF FDLWVKNLLI DSINWKNDLT NCINNTNVTD CKNDCNTNCK CFENWAKTKE NEWKKVK TI YKNENGNTNN YYKKLNNHFQ GYFFHVMKEL NKEEKWYKLM EDLKEKIDSS NLKNGTKDSE GAIKVLFDHL KDIAERCI D NNSKDSC

UniProtKB: Erythrocyte membrane protein 1, PfEMP1

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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
GridMaterial: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 130000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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