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- PDB-8dz4: Cryo-EM structure of 356 Fab in complex with recombinant shortene... -

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Basic information

Entry
Database: PDB / ID: 8dz4
TitleCryo-EM structure of 356 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
Components
  • 356 Fab heavy chain
  • 356 Fab light chain
  • Circumsporozoite protein
KeywordsIMMUNE SYSTEM / malaria antibody / PfCSP
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsMartin, G.M. / Ward, A.B.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationINV-004923 United States
CitationJournal: Nat Commun / Year: 2023
Title: Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection.
Authors: Gregory M Martin / Jonathan L Torres / Tossapol Pholcharee / David Oyen / Yevel Flores-Garcia / Grace Gibson / Re'em Moskovitz / Nathan Beutler / Diana D Jung / Jeffrey Copps / Wen-Hsin Lee ...Authors: Gregory M Martin / Jonathan L Torres / Tossapol Pholcharee / David Oyen / Yevel Flores-Garcia / Grace Gibson / Re'em Moskovitz / Nathan Beutler / Diana D Jung / Jeffrey Copps / Wen-Hsin Lee / Gonzalo Gonzalez-Paez / Daniel Emerling / Randall S MacGill / Emily Locke / C Richter King / Fidel Zavala / Ian A Wilson / Andrew B Ward /
Abstract: The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an ...The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family.
History
DepositionAug 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 2, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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
I: Circumsporozoite protein
L: 356 Fab light chain
H: 356 Fab heavy chain
B: 356 Fab light chain
A: 356 Fab heavy chain
D: 356 Fab light chain
C: 356 Fab heavy chain
F: 356 Fab light chain
E: 356 Fab heavy chain
N: 356 Fab light chain
M: 356 Fab heavy chain
P: 356 Fab light chain
O: 356 Fab heavy chain
R: 356 Fab light chain
Q: 356 Fab heavy chain
T: 356 Fab light chain
S: 356 Fab heavy chain
V: 356 Fab light chain
U: 356 Fab heavy chain
X: 356 Fab light chain
W: 356 Fab heavy chain
Z: 356 Fab light chain
Y: 356 Fab heavy chain


Theoretical massNumber of molelcules
Total (without water)556,48723
Polymers556,48723
Non-polymers00
Water0
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: 30232.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Production host: Escherichia coli (E. coli)
#2: Antibody
356 Fab light chain


Mass: 23165.775 Da / Num. of mol.: 11
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Antibody
356 Fab heavy chain


Mass: 24675.572 Da / Num. of mol.: 11
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
1356 Fab - rsCSP complexCOMPLEXall0RECOMBINANT
2Circumsporozoite proteinCOMPLEX#11RECOMBINANT
3356 Fab light chain, 356 Fab heavy chainCOMPLEX#2-#31RECOMBINANT
Molecular weightExperimental value: NO
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
21Cricetulus griseus (Chinese hamster)10029
32Escherichia 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: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 189641 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00220817
ELECTRON MICROSCOPYf_angle_d0.46628243
ELECTRON MICROSCOPYf_dihedral_angle_d4.1792903
ELECTRON MICROSCOPYf_chiral_restr0.042973
ELECTRON MICROSCOPYf_plane_restr0.0043706

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