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- PDB-8eh5: Cryo-EM structure of L9 Fab in complex with rsCSP -

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Basic information

Entry
Database: PDB / ID: 8eh5
TitleCryo-EM structure of L9 Fab in complex with rsCSP
Components
  • Circumsporozoite protein
  • L9 Heavy chain
  • L9 Light chain
KeywordsIMMUNE SYSTEM / PfCSP / malaria / antibody
Function / homology
Function and homology information


cell surface / plasma membrane / cytoplasm
Similarity search - Function
Plasmodium circumsporozoite protein / Thrombospondin type 1 domain / Thrombospondin type-1 (TSP1) repeat superfamily / Thrombospondin type-1 (TSP1) repeat profile. / Thrombospondin type 1 repeats / Thrombospondin type-1 (TSP1) repeat
Similarity search - Domain/homology
Circumsporozoite protein
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsMartin, G.M. / Ward, A.B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9.
Authors: Gregory M Martin / Monica L Fernández-Quintero / Wen-Hsin Lee / Tossapol Pholcharee / Lisa Eshun-Wilson / Klaus R Liedl / Marie Pancera / Robert A Seder / Ian A Wilson / Andrew B Ward /
Abstract: A primary objective in malaria vaccine design is the generation of high-quality antibody responses against the circumsporozoite protein of the malaria parasite, Plasmodium falciparum (PfCSP). To ...A primary objective in malaria vaccine design is the generation of high-quality antibody responses against the circumsporozoite protein of the malaria parasite, Plasmodium falciparum (PfCSP). To enable rational antigen design, we solved a cryo-EM structure of the highly potent anti-PfCSP antibody L9 in complex with recombinant PfCSP. We found that L9 Fab binds multivalently to the minor (NPNV) repeat domain, which is stabilized by a unique set of affinity-matured homotypic, antibody-antibody contacts. Molecular dynamics simulations revealed a critical role of the L9 light chain in integrity of the homotypic interface, which likely impacts PfCSP affinity and protective efficacy. These findings reveal the molecular mechanism of the unique NPNV selectivity of L9 and emphasize the importance of anti-homotypic affinity maturation in protective immunity against P. falciparum.
History
DepositionSep 13, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
G: Circumsporozoite protein
H: L9 Heavy chain
L: L9 Light chain
M: L9 Heavy chain
N: L9 Light chain
O: L9 Heavy chain
P: L9 Light chain


Theoretical massNumber of molelcules
Total (without water)174,5817
Polymers174,5817
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Circumsporozoite protein


Mass: 30363.354 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CS / Production host: Escherichia coli (E. coli) / References: UniProt: A0A5Q0MU09
#2: Antibody L9 Heavy chain


Mass: 24475.436 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Antibody L9 Light chain


Mass: 23597.254 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)

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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

Component
IDNameTypeEntity IDParent-IDSource
1trimeric complex of L9 Fab with rsCSPCOMPLEXall0RECOMBINANT
2Circumsporozoite proteinCOMPLEX#11RECOMBINANT
3L9 Heavy chain, L9 Light chainCOMPLEX#2-#31RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
23Homo sapiens (human)9606
12Plasmodium falciparum (malaria parasite P. falciparum)5833
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
23Cricetulus griseus (Chinese hamster)10029
12Escherichia coli (E. coli)562
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 60 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 451712 / Symmetry type: POINT

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