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- EMDB-28196: Cryo-EM structure of a potent anti-malarial antibody L9 in comple... -

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Basic information

Entry
Database: EMDB / ID: EMD-28196
TitleCryo-EM structure of a potent anti-malarial antibody L9 in complex with Plasmodium falciparum circumsporozoite protein (PfCSP)(class 2)
Map data
Sample
  • Complex: PfCSP in complex with antibody L9
    • Protein or peptide: Circumsporozoite protein
    • Protein or peptide: L9 Fab heavy chain
    • Protein or peptide: L9 Fab light chain
KeywordsAnti-Malarial / PfCSP / IMMUNE SYSTEM
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 / side of membrane / 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 speciesHomo sapiens (human) / Plasmodium falciparum 3D7 (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsTripathi P / Kwong PD
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Structure / Year: 2023
Title: Cryo-EM structures of anti-malarial antibody L9 with circumsporozoite protein reveal trimeric L9 association and complete 27-residue epitope.
Authors: Prabhanshu Tripathi / Michael F Bender / Haotian Lei / Lais Da Silva Pereira / Chen-Hsiang Shen / Brian Bonilla / Marlon Dillon / Li Ou / Marie Pancera / Lawrence T Wang / Baoshan Zhang / ...Authors: Prabhanshu Tripathi / Michael F Bender / Haotian Lei / Lais Da Silva Pereira / Chen-Hsiang Shen / Brian Bonilla / Marlon Dillon / Li Ou / Marie Pancera / Lawrence T Wang / Baoshan Zhang / Facundo D Batista / Azza H Idris / Robert A Seder / Peter D Kwong /
Abstract: Monoclonal antibody L9 recognizes the Plasmodium falciparum circumsporozoite protein (PfCSP) and is highly protective following controlled human malaria challenge. To gain insight into its function, ...Monoclonal antibody L9 recognizes the Plasmodium falciparum circumsporozoite protein (PfCSP) and is highly protective following controlled human malaria challenge. To gain insight into its function, we determined cryoelectron microscopy (cryo-EM) structures of L9 in complex with full-length PfCSP and assessed how this recognition influenced protection by wild-type and mutant L9s. Cryo-EM reconstructions at 3.6- and 3.7-Å resolution revealed L9 to recognize PfCSP as an atypical trimer. Each of the three L9s in the trimer directly recognized an Asn-Pro-Asn-Val (NPNV) tetrapeptide on PfCSP and interacted homotypically to facilitate L9-trimer assembly. We analyzed peptides containing different repeat tetrapeptides for binding to wild-type and mutant L9s to delineate epitope and homotypic components of L9 recognition; we found both components necessary for potent malaria protection. Last, we found the 27-residue stretch recognized by L9 to be highly conserved in P. falciparum isolates, suggesting the newly revealed complete L9 epitope to be an attractive vaccine target.
History
DepositionSep 20, 2022-
Header (metadata) releaseMar 15, 2023-
Map releaseMar 15, 2023-
UpdateSep 27, 2023-
Current statusSep 27, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28196.png

Downloads & links

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Map

FileDownload / File: emd_28196.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.92 Å
Density
Contour LevelBy AUTHOR: 0.266
Minimum - Maximum-1.1990021 - 2.2044454
Average (Standard dev.)0.000015098268 (±0.043702442)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 294.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_28196_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_28196_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : PfCSP in complex with antibody L9

EntireName: PfCSP in complex with antibody L9
Components
  • Complex: PfCSP in complex with antibody L9
    • Protein or peptide: Circumsporozoite protein
    • Protein or peptide: L9 Fab heavy chain
    • Protein or peptide: L9 Fab light chain

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Supramolecule #1: PfCSP in complex with antibody L9

SupramoleculeName: PfCSP in complex with antibody L9 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Circumsporozoite protein

MacromoleculeName: Circumsporozoite protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote) / Strain: isolate 3D7
Molecular weightTheoretical: 37.807488 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QEYQSYGSSS NTRVLNELNY DNAGTNLYNE LEMNYYGKQE NWYSLSSNSA SLGENDDGNN EDNEKLRKPK HKKLKQPADG NPDPNANPN VDPNANPNVD PNANPNVDPN ANPNANPNAN PNANPNANPN ANPNANPNAN PNANPNANPN ANPNANPNAN P NANPNANP ...String:
QEYQSYGSSS NTRVLNELNY DNAGTNLYNE LEMNYYGKQE NWYSLSSNSA SLGENDDGNN EDNEKLRKPK HKKLKQPADG NPDPNANPN VDPNANPNVD PNANPNVDPN ANPNANPNAN PNANPNANPN ANPNANPNAN PNANPNANPN ANPNANPNAN P NANPNANP NANPNANPNV DPNANPNANP NANPNANPNA NPNANPNANP NANPNANPNA NPNANPNANP NANPNANPNA NP NANPNAN PNANPNKNNQ GNGQGHNMPN DPNRNVDENA NANSAVKNNN NEEPSDKHIK EYLNKIQNSL STEWSPCSVT CGN GIQVRI KPGSANKPKD ELDYANDIEK KICKMEKCS

UniProtKB: Circumsporozoite protein

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Macromolecule #2: L9 Fab heavy chain

MacromoleculeName: L9 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.475436 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVKLVESGGG VVQPGRSLRL SCEASGFIFS TYGMHWVRQA PGKGLEWVAV IWFDGSNIYY ADSVKGRFTI SRDNSKNTVF MQMDSLRAE DTAVYYCHRN FYDGSGPFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
QVKLVESGGG VVQPGRSLRL SCEASGFIFS TYGMHWVRQA PGKGLEWVAV IWFDGSNIYY ADSVKGRFTI SRDNSKNTVF MQMDSLRAE DTAVYYCHRN FYDGSGPFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPKSCDKTH

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Macromolecule #3: L9 Fab light chain

MacromoleculeName: L9 Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.597254 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPST LSASVGDRVT ITCRASQFIS RWLAWYQQKP GKAPKLLIYK ASSLESGVPS RFSGSGSETH FTLTISSLQP DDVATYYCQ EYTSYGRTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPST LSASVGDRVT ITCRASQFIS RWLAWYQQKP GKAPKLLIYK ASSLESGVPS RFSGSGSETH FTLTISSLQP DDVATYYCQ EYTSYGRTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.3 µm / Nominal magnification: 45000
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 63.7 e/Å2

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7rqp

Initial angle assignmentType: NOT APPLICABLE
Final 3D classificationNumber classes: 2
Final angle assignmentType: NOT APPLICABLE
Final reconstructionNumber classes used: 3 / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2964341
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 137
Output model

PDB-8eka:
Cryo-EM structure of a potent anti-malarial antibody L9 in complex with Plasmodium falciparum circumsporozoite protein (PfCSP)(class 2)

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