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- EMDB-43150: Human monoclonal antibody C7 targeting HB3VAR03 (PfEMP1 A) -

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Basic information

Entry
Database: EMDB / ID: EMD-43150
TitleHuman monoclonal antibody C7 targeting HB3VAR03 (PfEMP1 A)
Map data
Sample
  • Complex: Human monoclonal antibody bound to HB3VAR03 PfEMP1 A
KeywordsMalaria / PfEMP1 / Human monoclonal antibodies / Severe malaria. / IMMUNE SYSTEM
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.0 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
DepositionDec 15, 2023-
Header (metadata) releaseOct 2, 2024-
Map releaseOct 2, 2024-
UpdateDec 18, 2024-
Current statusDec 18, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43150.png

Downloads & links

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Map

FileDownload / File: emd_43150.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 360 pix.
= 414. Å		1.15 Å/pix.
x 360 pix.
= 414. Å		1.15 Å/pix.
x 360 pix.
= 414. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.42
Minimum - Maximum-0.9029299 - 1.7796687
Average (Standard dev.)-0.00013153083 (±0.030380633)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 414.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_43150_half_map_1.map
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AxesZYX

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Half map: #2

Fileemd_43150_half_map_2.map
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Sample components

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Entire : Human monoclonal antibody bound to HB3VAR03 PfEMP1 A

EntireName: Human monoclonal antibody bound to HB3VAR03 PfEMP1 A
Components
  • Complex: Human monoclonal antibody bound to HB3VAR03 PfEMP1 A

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Supramolecule #1: Human monoclonal antibody bound to HB3VAR03 PfEMP1 A

SupramoleculeName: Human monoclonal antibody bound to HB3VAR03 PfEMP1 A / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)

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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 TECNAI ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 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: 1.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 75000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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