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- PDB-6mhg: Cryo-EM structure of the circumsporozoite protein of Plasmodium f... -

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Basic information

Entry
Database: PDB / ID: 6mhg
TitleCryo-EM structure of the circumsporozoite protein of Plasmodium falciparum with a vaccine-elicited antibody reveals maturation of inter-antibody contacts
Components
  • Fab311 heavy chain
  • Fab311 light chain
  • circumsporozoite protein
KeywordsIMMUNE SYSTEM / Plasmodium falciparum / antibody / CSP / rsCSP
Function / homology
Function and homology information


host cell surface binding / symbiont entry into host / entry into host cell by a symbiont-containing vacuole / heparan sulfate proteoglycan binding / immunoglobulin complex / side of membrane / adaptive immune response / 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 / : / Immunoglobulin V-Type / Immunoglobulin V-set domain ...: / 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 / : / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Circumsporozoite protein / Epididymis luminal protein 214
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.57 Å
AuthorsCottrell, C.A. / Torres, J.L. / Ward, A.B.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationOPP1170236 United States
CitationJournal: Sci Adv / Year: 2018
Title: Cryo-EM structure of circumsporozoite protein with a vaccine-elicited antibody is stabilized by somatically mutated inter-Fab contacts.
Authors: David Oyen / Jonathan L Torres / Christopher A Cottrell / C Richter King / Ian A Wilson / Andrew B Ward /
Abstract: The circumsporozoite protein (CSP) on the surface of sporozoites is important for parasite development, motility, and host hepatocyte invasion. However, intrinsic disorder of the NANP repeat ...The circumsporozoite protein (CSP) on the surface of sporozoites is important for parasite development, motility, and host hepatocyte invasion. However, intrinsic disorder of the NANP repeat sequence in the central region of CSP has hindered its structural and functional characterization. Here, the cryo-electron microscopy structure at ~3.4-Å resolution of a recombinant shortened CSP construct with the variable domains (Fabs) of a highly protective monoclonal antibody reveals an extended spiral conformation of the central NANP repeat region surrounded by antibodies. This unusual structure appears to be stabilized and/or induced by interaction with an antibody where contacts between adjacent Fabs are somatically mutated and enhance the interaction. This maturation in non-antigen contact residues may be an effective mechanism for antibodies to target tandem repeat sequences and provide novel insights into malaria vaccine design.
History
DepositionSep 17, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Structure visualization

Movie
  • Deposited structure unit
  • Imaged by Jmol
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  • Superimposition on EM map
  • EMDB-9114
  • Imaged by UCSF Chimera
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Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: circumsporozoite protein
H: Fab311 heavy chain
L: Fab311 light chain
A: Fab311 heavy chain
N: Fab311 light chain
B: Fab311 heavy chain
O: Fab311 light chain
C: Fab311 heavy chain
P: Fab311 light chain
D: Fab311 heavy chain
Q: Fab311 light chain
F: Fab311 heavy chain
R: Fab311 light chain
G: Fab311 heavy chain
S: Fab311 light chain
I: Fab311 heavy chain
T: Fab311 light chain
J: Fab311 heavy chain
U: Fab311 light chain
K: Fab311 heavy chain
V: Fab311 light chain
M: Fab311 heavy chain
W: Fab311 light chain


Theoretical massNumber of molelcules
Total (without water)548,10523
Polymers548,10523
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area41410 Å2
ΔGint-173 kcal/mol
Surface area102980 Å2

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Components

#1: Protein circumsporozoite protein


Mass: 30232.156 Da / Num. of mol.: 1 / Fragment: shortened construct
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Production host: Escherichia coli (E. coli) / References: UniProt: Q7K740*PLUS
#2: Antibody
Fab311 heavy chain


Mass: 24098.877 Da / Num. of mol.: 11
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: V9HW68
#3: Antibody
Fab311 light chain


Mass: 22980.484 Da / Num. of mol.: 11
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
Has protein modificationY

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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
1Fab311 in complex with Plasmodium falciparum recombinant shortened CSPCOMPLEXall0MULTIPLE SOURCES
2Plasmodium falciparum recombinant shortened CSPCOMPLEX#11RECOMBINANT
3Fab311COMPLEX#2-#31RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Plasmodium falciparum (malaria parasite P. falciparum)5833
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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 magnification: 29000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 12 sec. / Electron dose: 62 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1497
Image scansSampling size: 5 µm / Width: 3710 / Height: 3838 / Movie frames/image: 48 / Used frames/image: 0-47

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Processing

EM software
IDNameVersionCategory
1Gautomatchparticle selection
2Leginonimage acquisition
4GctfCTF correction
7UCSF Chimeramodel fitting
9RosettaEMmodel refinement
12cryoSPARCclassification
13RELION2.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 312806
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 206990 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL / Target criteria: EMRinger
Atomic model building

3D fitting-ID: 1 / Accession code: 6AXK / Initial refinement model-ID: 1 / PDB-ID: 6AXK

6axk

/ Source name: PDB / Type: experimental model

IDPdb chain-ID
1A
2B
3E

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