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- EMDB-43148: Cryo-EM structure of human monoclonal antibody C7 targeting IT4VA... -

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Basic information

Entry
Database: EMDB / ID: EMD-43148
TitleCryo-EM structure of human monoclonal antibody C7 targeting IT4VAR22 CIDRa1.7 (PfEMP1 A)
Map data
Sample
  • Complex: Plasmodium falciparum Erythrocyte Membrane Protein 1 complexed with human monoclonal antibody
    • Protein or peptide: Erythrocyte membrane protein 1
    • Protein or peptide: C7 Fab heavy chain
    • Protein or peptide: C7 Fab lamda chain
KeywordsMalaria / PfEMP1 / Human monoclonal antibodies / Severe 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: 3.5 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_43148.png

Downloads & links

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Map

FileDownload / File: emd_43148.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 384 pix.
= 278.4 Å		0.73 Å/pix.
x 384 pix.
= 278.4 Å		0.73 Å/pix.
x 384 pix.
= 278.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.725 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.59768903 - 0.92959756
Average (Standard dev.)0.000015961645 (±0.010167269)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 278.40002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_43148_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_43148_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Plasmodium falciparum Erythrocyte Membrane Protein 1 complexed wi...

EntireName: Plasmodium falciparum Erythrocyte Membrane Protein 1 complexed with human monoclonal antibody
Components
  • Complex: Plasmodium falciparum Erythrocyte Membrane Protein 1 complexed with human monoclonal antibody
    • Protein or peptide: Erythrocyte membrane protein 1
    • Protein or peptide: C7 Fab heavy chain
    • Protein or peptide: C7 Fab lamda chain

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Supramolecule #1: Plasmodium falciparum Erythrocyte Membrane Protein 1 complexed wi...

SupramoleculeName: Plasmodium falciparum Erythrocyte Membrane Protein 1 complexed with human monoclonal antibody
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 190 kDa/nm

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Macromolecule #1: Erythrocyte membrane protein 1

MacromoleculeName: Erythrocyte membrane protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)
Molecular weightTheoretical: 133.706328 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSQSSKPSK PSVDTNESYK SARNVLERYA ESIKQQAEND ASGYEKELKG KLEEASFCGA YCELIGVPKY GSTDPCYLDH RWHTNLLHE KVKDRDPCHN RNQKRFDEGR VYECGSGIIK GNGNNRNGGS CAPPRRRHMC DKNLEALTVA NTKNSNDLLG N ILVTAKYE ...String:
MGSQSSKPSK PSVDTNESYK SARNVLERYA ESIKQQAEND ASGYEKELKG KLEEASFCGA YCELIGVPKY GSTDPCYLDH RWHTNLLHE KVKDRDPCHN RNQKRFDEGR 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 KLGNVKKACR 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 HAKACNC

UniProtKB: Erythrocyte membrane protein 1

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Macromolecule #2: C7 Fab heavy chain

MacromoleculeName: C7 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.871637 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EVQLVESGGG LAQPGGSLRL SCAASGFTFR DHGMTWVRQV SGKGLEWLSY ITAGSKMSYY SDSVRGRFTI SRDNAKNSLY LQMNGLTDE DSAIYYCVKG GGNCPSDTCY PSGYFGLDVW GQGTTVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK D YFPEPVTV ...String:
EVQLVESGGG LAQPGGSLRL SCAASGFTFR DHGMTWVRQV SGKGLEWLSY ITAGSKMSYY SDSVRGRFTI SRDNAKNSLY LQMNGLTDE DSAIYYCVKG GGNCPSDTCY PSGYFGLDVW GQGTTVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK D YFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKKV

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Macromolecule #3: C7 Fab lamda chain

MacromoleculeName: C7 Fab lamda chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.939492 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QSELTQPPSM SVSPGQTAMI TCSMNKYSYI SWYQQRPGQS PALVIYQDTR RPSGIPERFS GSNSENTAIL TITGTRDLDE ADYFCQGWD SNVKAVLFGG GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS ...String:
QSELTQPPSM SVSPGQTAMI TCSMNKYSYI SWYQQRPGQS PALVIYQDTR RPSGIPERFS GSNSENTAIL TITGTRDLDE ADYFCQGWD SNVKAVLFGG GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS

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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

Concentration0.45 mg/mL
BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277 K / 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 / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm

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Image processing

Startup modelType of model: INSILICO MODEL / In silico model: Alphafold2, Abodybuilder2
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 80835
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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