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- EMDB-49201: Cryo-EM structure of 110_C4 Fab in complex with CIDRa1.7 PfEMP1 -

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Basic information

Entry
Database: EMDB / ID: EMD-49201
TitleCryo-EM structure of 110_C4 Fab in complex with CIDRa1.7 PfEMP1
Map data
Sample
  • Complex: Complex of human serum antibody 110_C4 with CIDRa1.7 PfEMP1
    • Protein or peptide: 110_C4 Fab heavy chain
    • Protein or peptide: 110_C4 Fab light chain
    • Protein or peptide: Erythrocyte membrane protein 1
KeywordsSerum antibody / Cryo-EM / Monoclonal antibody / PfEMP1 / Malaria / IMMUNE SYSTEM
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsRaghavan SSR / Ward AB
Funding support United States, Denmark, 2 items
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, 2025-
Header (metadata) releaseAug 27, 2025-
Map releaseAug 27, 2025-
UpdateAug 27, 2025-
Current statusAug 27, 2025Processing site: RCSB / Status: Released

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Structure visualization

Downloads & links

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Map

FileDownload / File: emd_49201.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.725 Å
Density
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.6782225 - 0.9686831
Average (Standard dev.)0.00013777708 (±0.012453695)
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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Sample components

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Entire : Complex of human serum antibody 110_C4 with CIDRa1.7 PfEMP1

EntireName: Complex of human serum antibody 110_C4 with CIDRa1.7 PfEMP1
Components
  • Complex: Complex of human serum antibody 110_C4 with CIDRa1.7 PfEMP1
    • Protein or peptide: 110_C4 Fab heavy chain
    • Protein or peptide: 110_C4 Fab light chain
    • Protein or peptide: Erythrocyte membrane protein 1

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Supramolecule #1: Complex of human serum antibody 110_C4 with CIDRa1.7 PfEMP1

SupramoleculeName: Complex of human serum antibody 110_C4 with CIDRa1.7 PfEMP1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 110_C4 Fab heavy chain

MacromoleculeName: 110_C4 Fab heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.228796 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
QVHLVQSGAE VKKPGSSATV SCKASGGPFR GYSVSWVRQA PGQGLEWMGQ IITMLDTITY AQRFQDRVTI RADETTSTIY MELNSLRSE DTAIYYCARN GNATVGSLGM DVWGRGTTVT VSS

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Macromolecule #2: 110_C4 Fab light chain

MacromoleculeName: 110_C4 Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.888984 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
QAGLTQPPSE SKGLRETATF TCTGNSNNVG NQGAAWLQQH QGHPPKLLSY RNNNRPSGIS ERFSASRSGN TASLTITGLQ PEDEAVYFC SAWDTSLRAW LFGGGTHLTV LG

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Macromolecule #3: Erythrocyte membrane protein 1

MacromoleculeName: Erythrocyte membrane protein 1 / type: protein_or_peptide / ID: 3 / Details: CIDRa1.7 PfEMP1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)
Molecular weightTheoretical: 138.359141 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSQSSKPSK PSVDTNESYK SARNVLERYA ESIKQQAEND ASGYEKELKG KLEEASFCGA YCELIGVPKY GSTDPCYLDH RWHTNLLHE KVKDRDPCHN RNQKRFDEGQ VYECGSGIIK GNGNNRNGGS CAPPRRRHMC DKNLEALTVA NTKNSNDLLG N ILVTAKYE ...String:
MGSQSSKPSK PSVDTNESYK SARNVLERYA ESIKQQAEND ASGYEKELKG KLEEASFCGA YCELIGVPKY GSTDPCYLDH RWHTNLLHE KVKDRDPCHN RNQKRFDEGQ VYECGSGIIK GNGNNRNGGS CAPPRRRHMC DKNLEALTVA NTKNSNDLLG N ILVTAKYE GDSIVNSYAN SGMFNVCTAL ARSFADIGDI IRGKDLYLGN GDYKEKVSNN LRAIFNKIYE NLNDPNVKAH YQ KDAPNYY KLREHWWTVN RDQVWKAITC NAPTGADYFR KGSDGTNVFT SQGQCGHYEG APPTNLDYVP QFLRWFEEWA EEF CRKKKI KLENVKKACR DESSKLYCSH NGYDCTQTIR NKDICIRESK CTDCSTKCKL YELWLEKQEN EFKKQTKKYD KEIN GNNSL QNNKNNGIDK KYHNEFYKNF REKGYTSLDK FLKLLNEGMY CKNQKPEEED IDFTKNGDKG IFYRSEYCQV CPYCG LDCG GKTCTAKQEI YPDCVYNGAY EPPNGAETTE ITVLYSADQE GDISNKLSEF CNDENNKNSQ KWQCYYVSSE NNGCKM EKK NANHTPEVKI TKFHNFFEMW VTYLLTETIT WKDKLKTCMN NTKTADCIHE CNKNCVCFDK WVKQKEDEWN SIKKLFT KE KKMPKQYYGN INIYFESFFF HVMKKLNKEA KWNKLMDELR NKIELSKGNE GTKDLQDAIE LLLEYLKEKS TICKDNNT N EACDPTVDPT KNPCGKNTKA GSDKVISVKQ IAQYYKRLAH EQLEERGSRS ALKGDASKGT YRRQGNPRKL KKVCRIAKD HSNRNHKDSR GRHLCTSYLE FLQTIDDSHN SSNAKRVNNS FLGDVLLSAK LDAAEIIKRY KDQNNIRENI EQKDEEAMCR AVRYSFADL GDIIRGKDLW DHKDFKKLER DLVKIFGKIK DELKSKLGDK YIGDEAKSPY KQLRSDWWEA NRHQVWKAMQ C KTTTKPFS LNIKCGDTSI TPLVDYIPQR LRWMTEWAEW YCKEQSRLYG ELVEKCNTCG SSNGIVTTED CKKKCMQCKQ KC EAYKSFI EKWKKQWDEQ EKKYQELYRK ATQNGSDGSK VTADKDADVV DFLSKLRNKN DTNNLFESAA AYVHDTGNLD DCN AQNIFC EKNCDGKVND KYVFRKYPYD HAKACNCNEN VTPRPPALSN GSGSHHHHHH GSGSGLNDIF EAQKIEWHE

UniProtKB: Erythrocyte membrane protein 1

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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

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 49.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 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: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 394495
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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