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- PDB-9naq: Cryo-EM structure of 110_C4 Fab in complex with CIDRa1.7 PfEMP1 -

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Basic information

Entry
Database: PDB / ID: 9naq
TitleCryo-EM structure of 110_C4 Fab in complex with CIDRa1.7 PfEMP1
Components
  • 110_C4 Fab heavy chain
  • 110_C4 Fab light chain
  • Erythrocyte membrane protein 1
KeywordsIMMUNE SYSTEM / Serum antibody / Cryo-EM / Monoclonal antibody / PfEMP1 / Malaria
Function / homology
Function and homology information


host cell surface receptor binding / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Plasmodium falciparum (malaria parasite P. falciparum)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsRaghavan, S.S.R. / Ward, A.B.
Funding support United States, Denmark, 2items
OrganizationGrant numberCountry
Bill & Melinda Gates Foundation United States
Novo Nordisk Foundation Denmark
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Identification of broadly inhibitory anti-PfEMP1 antibodies by mass spectrometry sequencing of plasma IgG from a malaria-exposed child.
Authors: Louise Turner / Teresa Nunez de Villavicencio Diaz / Sai Sundar Rajan Raghavan / Ikhlaq Hussain Kana / Eric Lyimo / Chelsea Reitzel / Christian W Wang / Ewen Berube / Rasmus W Jensen / ...Authors: Louise Turner / Teresa Nunez de Villavicencio Diaz / Sai Sundar Rajan Raghavan / Ikhlaq Hussain Kana / Eric Lyimo / Chelsea Reitzel / Christian W Wang / Ewen Berube / Rasmus W Jensen / Johannes R Loeffler / Monica Lisa Fernández-Quintero / Thor G Theander / John P A Lusingu / Thierry Le Bihan / Xiaobing Han / Daniel T R Minja / Andrew B Ward / Bin Ma / Thomas Lavstsen /
Abstract: pathology is driven by the accumulation of parasite-infected erythrocytes in blood capillaries. This sequestration process is mediated by the parasite's erythrocyte membrane protein 1 (PfEMP1) ... pathology is driven by the accumulation of parasite-infected erythrocytes in blood capillaries. This sequestration process is mediated by the parasite's erythrocyte membrane protein 1 (PfEMP1) adhesins, which bind select endothelial cell receptors. A subset of PfEMP1 binding human endothelial protein C receptor (EPCR) through their cysteine-rich interdomain region alpha 1 (CIDRα1) domains drives the pathogenesis to severe malaria. Despite high sequence diversity among CIDRα1 domains, individuals living in malaria-endemic regions become immune to severe disease in part through acquisition of antibodies inhibiting the PfEMP1-EPCR interaction. Here, we demonstrate an approach to identify pathogen-specific human monoclonal antibodies from plasma, combining mass spectrometry analysis of antigen-purified polyclonal plasma IgG and Ig transcript sequencing. We identified a clonal family of broadly reactive and EPCR binding-inhibitory human monoclonal antibodies against CIDRα1. The antibodies, isolated from a 9-y-old child, exhibited potent inhibition of EPCR binding broadly across CIDRα1 domains as well as binding of infected erythrocytes to EPCR. Structural analysis of one antibody variant complexed with CIDRα1 revealed a shared epitope of the clonal antibody family overlapping the EPCR binding site and the epitopes of two previously identified monoclonal antibodies, C7 and C74, with similar functional patterns. However, although C7, C74, and 110-3 antibodies all depend on the same few residues conserved in CIDRα1 to retain EPCR binding, the 110-3 antibodies contact additional variable residues, reducing their breadth of reactivity across the CIDRα1 family. These data bolster the hypothesis that broadly inhibitory antibodies against severe malaria-associated PfEMP1 target similar epitopes and are commonly developed in malaria-exposed individuals.
History
DepositionFeb 12, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 27, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
H: 110_C4 Fab heavy chain
L: 110_C4 Fab light chain
A: Erythrocyte membrane protein 1


Theoretical massNumber of molelcules
Total (without water)163,4773
Polymers163,4773
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: Antibody 110_C4 Fab heavy chain


Mass: 13228.796 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody 110_C4 Fab light chain


Mass: 11888.984 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein Erythrocyte membrane protein 1


Mass: 138359.141 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: CIDRa1.7 PfEMP1
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: IT4_var22 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A3R6S4
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

ComponentName: Complex of human serum antibody 110_C4 with CIDRa1.7 PfEMP1
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
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

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 49 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21_5207 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 394495 / Symmetry type: POINT
RefinementHighest resolution: 3.4 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0042576
ELECTRON MICROSCOPYf_angle_d0.6233482
ELECTRON MICROSCOPYf_dihedral_angle_d14.871920
ELECTRON MICROSCOPYf_chiral_restr0.044381
ELECTRON MICROSCOPYf_plane_restr0.004438

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