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- EMDB-27784: Cryo-EM structure of 239 Fab in complex with recombinant shortene... -

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Basic information

Entry
Database: EMDB / ID: EMD-27784
TitleCryo-EM structure of 239 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
Map dataCryo-EM structure of 239 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
Sample
  • Complex: 239 Fab - rsCSP complex
    • Complex: Circumsporozoite protein
      • Protein or peptide: Circumsporozoite protein
    • Complex: 239 Fab light chain, 239 Fab heavy chain
      • Protein or peptide: 239 Fab light chain
      • Protein or peptide: 239 Fab heavy chain
Keywordsmalaria antibody / PfCSP / IMMUNE SYSTEM
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.72 Å
AuthorsMartin GM / Ward AB
Funding support United States, 1 items
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 5, 2022-
Header (metadata) releaseAug 2, 2023-
Map releaseAug 2, 2023-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27784.png

Downloads & links

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Map

FileDownload / File: emd_27784.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of 239 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 220 pix.
= 253. Å		1.15 Å/pix.
x 220 pix.
= 253. Å		1.15 Å/pix.
x 220 pix.
= 253. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-1.7672147 - 3.4643211
Average (Standard dev.)-0.0030634454 (±0.14999774)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 253.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM structure of 239 Fab in complex with...

Fileemd_27784_half_map_1.map
AnnotationCryo-EM structure of 239 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM structure of 239 Fab in complex with...

Fileemd_27784_half_map_2.map
AnnotationCryo-EM structure of 239 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : 239 Fab - rsCSP complex

EntireName: 239 Fab - rsCSP complex
Components
  • Complex: 239 Fab - rsCSP complex
    • Complex: Circumsporozoite protein
      • Protein or peptide: Circumsporozoite protein
    • Complex: 239 Fab light chain, 239 Fab heavy chain
      • Protein or peptide: 239 Fab light chain
      • Protein or peptide: 239 Fab heavy chain

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Supramolecule #1: 239 Fab - rsCSP complex

SupramoleculeName: 239 Fab - rsCSP complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Circumsporozoite protein

SupramoleculeName: Circumsporozoite protein / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)

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Supramolecule #3: 239 Fab light chain, 239 Fab heavy chain

SupramoleculeName: 239 Fab light chain, 239 Fab heavy chain / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
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 (malaria parasite P. falciparum)
Molecular weightTheoretical: 30.232156 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: YGSSSNTRVL NELNYDNAGT NLYNELEMNY YGKQENWYSL KKNSRSLGEN DDGNNEDNEK LRKPKHKKLK QPADGNPDPN ANPNVDPNA NPNVDPNANP NVDPNANPNA NPNANPNANP NANPNANPNA NPNANPNANP NANPNANPNA NPNANPNANP N ANPNANPN ...String:
YGSSSNTRVL NELNYDNAGT NLYNELEMNY YGKQENWYSL KKNSRSLGEN DDGNNEDNEK LRKPKHKKLK QPADGNPDPN ANPNVDPNA NPNVDPNANP NVDPNANPNA NPNANPNANP NANPNANPNA NPNANPNANP NANPNANPNA NPNANPNANP N ANPNANPN KNNQGNGQGH NMPNDPNRNV DENANANSAV KNNNNEEPSD KHIKEYLNKI QNSLSTEWSP CSVTCGNGIQ VR IKPGSAN KPKDELDYAN DIEKKICKME KCSSVFNVVN S

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Macromolecule #2: 239 Fab light chain

MacromoleculeName: 239 Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.614164 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPST LSASVGDRVT ITCRASQSVS TSLAWYQQKP GKAPNLLIYQ ASTLYRGVPS RFSGSGSGTE FTLTIGSLQP DDFATYYCQ HYNSYSRITF GQGTRLEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
DIQMTQSPST LSASVGDRVT ITCRASQSVS TSLAWYQQKP GKAPNLLIYQ ASTLYRGVPS RFSGSGSGTE FTLTIGSLQP DDFATYYCQ HYNSYSRITF GQGTRLEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #3: 239 Fab heavy chain

MacromoleculeName: 239 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.630812 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVESGGG VVQPGRSLRL SCAASRLTFR NFGMHWVRQT PGKGLEWVAV IWHDGSNKFY ADSVEGRFTI SRDNSKNTLY LQMNSLRDE DTAIYYCAKD WGGASDRVFD YWGRGTLVIV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT ...String:
QVQLVESGGG VVQPGRSLRL SCAASRLTFR NFGMHWVRQT PGKGLEWVAV IWHDGSNKFY ADSVEGRFTI SRDNSKNTLY LQMNSLRDE DTAIYYCAKD WGGASDRVFD YWGRGTLVIV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL LG GPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNG KEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP PSRDELTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPP VLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPG

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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

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Electron microscopy

MicroscopeFEI TECNAI ARCTICA
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.72 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 227439
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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