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- EMDB-27787: Cryo-EM structure of 337 Fab in complex with recombinant shortene... -

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Entry
Database: EMDB / ID: EMD-27787
TitleCryo-EM structure of 337 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
Map dataCryo-EM structure of 337 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
Sample
  • Complex: 337 Fab - rsCSP complex
    • Complex: Circumsporozoite protein
      • Protein or peptide: Circumsporozoite protein
    • Complex: 337 Fab heavy chain, 337 Fab light chain
      • Protein or peptide: 337 Fab heavy chain
      • Protein or peptide: 337 Fab light chain
Keywordsmalaria antibody / PfCSP / IMMUNE SYSTEM
Biological speciesEscherichia coli (E. coli) / Homo sapiens (human) / Plasmodium falciparum (malaria parasite P. falciparum)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 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 6, 2022-
Header (metadata) releaseAug 2, 2023-
Map releaseAug 2, 2023-
UpdateApr 24, 2024-
Current statusApr 24, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27787.png

Downloads & links

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Map

FileDownload / File: emd_27787.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of 337 Fab in complex with recombinant shortened Plasmodium falciparum circumsporozoite protein (rsCSP)
Voxel sizeX=Y=Z: 1.026 Å
Density
Contour LevelBy EMDB: 0.5
Minimum - Maximum-4.893802 - 8.2433
Average (Standard dev.)-0.05538445 (±0.21750578)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 225.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM structure of 337 Fab in complex with...

Fileemd_27787_half_map_1.map
AnnotationCryo-EM structure of 337 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 337 Fab in complex with...

Fileemd_27787_half_map_2.map
AnnotationCryo-EM structure of 337 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 : 337 Fab - rsCSP complex

EntireName: 337 Fab - rsCSP complex
Components
  • Complex: 337 Fab - rsCSP complex
    • Complex: Circumsporozoite protein
      • Protein or peptide: Circumsporozoite protein
    • Complex: 337 Fab heavy chain, 337 Fab light chain
      • Protein or peptide: 337 Fab heavy chain
      • Protein or peptide: 337 Fab light chain

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Supramolecule #1: 337 Fab - rsCSP complex

SupramoleculeName: 337 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: Escherichia coli (E. coli)

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Supramolecule #3: 337 Fab heavy chain, 337 Fab light chain

SupramoleculeName: 337 Fab heavy chain, 337 Fab light 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: 337 Fab heavy chain

MacromoleculeName: 337 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 7 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.31923 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVESGGG VVQPGRSLRL SCAASGFSFS TYGMHWVRQA PGKGLEWVAL IWHDGSKKFY SESVRGRFTI SRDNSMDTLY LQMSSLRAE DTAVYYCARD GADYFDSTGG AFDIWGQGTM VIVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
QVQLVESGGG VVQPGRSLRL SCAASGFSFS TYGMHWVRQA PGKGLEWVAL IWHDGSKKFY SESVRGRFTI SRDNSMDTLY LQMSSLRAE DTAVYYCARD GADYFDSTGG AFDIWGQGTM VIVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCD

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Macromolecule #3: 337 Fab light chain

MacromoleculeName: 337 Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 7 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.321887 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EIVMTQSPAT LSVSPGERAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYG ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFATYYCQ QYKTWWTFGQ GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK ...String:
EIVMTQSPAT LSVSPGERAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYG ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFATYYCQ QYKTWWTFGQ GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC

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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 TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 461179

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