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- PDB-7z12: VAR2 complex with PAM1.4 -

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Basic information

Entry
Database: PDB / ID: 7z12
TitleVAR2 complex with PAM1.4
Components
  • PAM1.4, Heavy Chain
  • PAM1.4, light Chain
  • VAR2CSA
KeywordsCELL ADHESION / VAR2CSA / malaria
Function / homology
Function and homology information


membrane => GO:0016020 / host cell surface receptor binding
Similarity search - Function
Plasmodium falciparum erythrocyte membrane protein 1, N-terminal / N-terminal segments of P. falciparum erythrocyte membrane protein / 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
Biological speciesHomo sapiens (human)
Plasmodium falciparum (malaria parasite P. falciparum)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsRaghavan, S.S.R. / Wang, K.T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: PLoS Pathog / Year: 2022
Title: Cryo-EM reveals the conformational epitope of human monoclonal antibody PAM1.4 broadly reacting with polymorphic malarial protein VAR2CSA.
Authors: Sai Sundar Rajan Raghavan / Robert Dagil / Mary Lopez-Perez / Julian Conrad / Maria Rosaria Bassi / Maria Del Pilar Quintana / Swati Choudhary / Tobias Gustavsson / Yong Wang / Pontus ...Authors: Sai Sundar Rajan Raghavan / Robert Dagil / Mary Lopez-Perez / Julian Conrad / Maria Rosaria Bassi / Maria Del Pilar Quintana / Swati Choudhary / Tobias Gustavsson / Yong Wang / Pontus Gourdon / Michael Fokuo Ofori / Sebastian Boje Christensen / Daniel Thomas Remias Minja / Christentze Schmiegelow / Morten Agertoug Nielsen / Lea Barfod / Lars Hviid / Ali Salanti / Thomas Lavstsen / Kaituo Wang /
Abstract: Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. ...Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. Immunity to placental malaria is acquired through exposure and mediated through antibodies to VAR2CSA. Through evolution, the VAR2CSA proteins have diversified in sequence to escape immune recognition but retained their overall macromolecular structure to maintain CS binding affinity. This structural conservation may also have allowed development of broadly reactive antibodies to VAR2CSA in immune women. Here we show the negative stain and cryo-EM structure of the only known broadly reactive human monoclonal antibody, PAM1.4, in complex with VAR2CSA. The data shows how PAM1.4's broad VAR2CSA reactivity is achieved through interactions with multiple conserved residues of different sub-domains forming conformational epitope distant from the CS binding site on the VAR2CSA core structure. Thus, while PAM1.4 may represent a class of antibodies mediating placental malaria immunity by inducing phagocytosis or NK cell-mediated cytotoxicity, it is likely that broadly CS binding-inhibitory antibodies target other epitopes at the CS binding site. Insights on both types of broadly reactive monoclonal antibodies may aid the development of a vaccine against placental malaria.
History
DepositionFeb 24, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: PAM1.4, Heavy Chain
C: PAM1.4, light Chain
A: VAR2CSA


Theoretical massNumber of molelcules
Total (without water)312,3393
Polymers312,3393
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area6070 Å2
ΔGint-25 kcal/mol
Surface area97410 Å2

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Components

#1: Antibody PAM1.4, Heavy Chain


Mass: 51554.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#2: Antibody PAM1.4, light Chain


Mass: 25425.562 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#3: Protein VAR2CSA


Mass: 235359.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Strain: FVO / Gene: PFFVO_03259 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A024V5I6

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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: VAR2CSA complex with PAM1.4 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.35 MDa / Experimental value: NO
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM software
IDNameCategory
2EPUimage acquisition
4cryoSPARCCTF correction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 50000 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00618711
ELECTRON MICROSCOPYf_angle_d0.93125210
ELECTRON MICROSCOPYf_dihedral_angle_d9.2522581
ELECTRON MICROSCOPYf_chiral_restr0.0542645
ELECTRON MICROSCOPYf_plane_restr0.0063268

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