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- PDB-8vdl: HB3VAR03 CIDRa1.4 domain with C7 Fab -

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Basic information

Entry
Database: PDB / ID: 8vdl
TitleHB3VAR03 CIDRa1.4 domain with C7 Fab
Components
  • C7 Heavy Chain
  • C7 Light Chain
  • HB3VAR03 CIDRa1.4 domain
KeywordsIMMUNE SYSTEM / Malaria / Plasmodium falciparum / PfEMP1
Biological speciesPlasmodium falciparum HB3 (eukaryote)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.68 Å
AuthorsHurlburt, N.K. / Pancera, M.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates Foundation United States
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: HB3VAR03 CIDRa1.4 domain
H: C7 Heavy Chain
L: C7 Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,4739
Polymers68,0803
Non-polymers3926
Water2,522140
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5360 Å2
ΔGint-164 kcal/mol
Surface area24150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.653, 65.353, 250.341
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein HB3VAR03 CIDRa1.4 domain


Mass: 19549.170 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum HB3 (eukaryote) / Cell line (production host): Expi293F / Production host: Homo sapiens (human)
#2: Antibody C7 Heavy Chain


Mass: 25591.521 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK 293E / Production host: Homo sapiens (human)
#3: Protein C7 Light Chain


Mass: 22939.492 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK 293E / Production host: Homo sapiens (human)
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 140 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.34 Å3/Da / Density % sol: 63.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 0.1M MES, pH 6.0, 0.2M Zn Acetate, 10% PEG 8K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.97387 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97387 Å / Relative weight: 1
ReflectionResolution: 2.68→50.07 Å / Num. obs: 26449 / % possible obs: 99.6 % / Redundancy: 9.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.143 / Rpim(I) all: 0.049 / Rrim(I) all: 0.151 / Χ2: 0.98 / Net I/σ(I): 11.2 / Num. measured all: 250859
Reflection shellResolution: 2.68→2.81 Å / % possible obs: 97.8 % / Redundancy: 9.3 % / Rmerge(I) obs: 1.531 / Num. measured all: 31447 / Num. unique obs: 3368 / CC1/2: 0.656 / Rpim(I) all: 0.523 / Rrim(I) all: 1.621 / Χ2: 0.8 / Net I/σ(I) obs: 1.6

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata scaling
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.68→46.3 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 27.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2659 1350 5.12 %RANDOM
Rwork0.2167 ---
obs0.2192 26372 99.57 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.68→46.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3921 0 6 140 4067
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008
X-RAY DIFFRACTIONf_angle_d1.061
X-RAY DIFFRACTIONf_dihedral_angle_d181433
X-RAY DIFFRACTIONf_chiral_restr0.057604
X-RAY DIFFRACTIONf_plane_restr0.018692
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.68-2.780.38231320.29412374X-RAY DIFFRACTION97
2.78-2.890.32921270.2652454X-RAY DIFFRACTION100
2.89-3.020.32671380.24182459X-RAY DIFFRACTION100
3.02-3.180.25211460.22512478X-RAY DIFFRACTION100
3.18-3.380.27831330.21242472X-RAY DIFFRACTION100
3.38-3.640.27341270.21122501X-RAY DIFFRACTION100
3.64-4.010.24591400.20632499X-RAY DIFFRACTION100
4.01-4.590.23741340.17422520X-RAY DIFFRACTION100
4.59-5.780.20131280.18012567X-RAY DIFFRACTION100
5.78-46.30.25981450.23592698X-RAY DIFFRACTION100

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