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- EMDB-22879: cryoEM structure of LILRB1 D3D4 domain-inserted antibody MDB1 Fab... -

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Basic information

Entry
Database: EMDB / ID: EMD-22879
TitlecryoEM structure of LILRB1 D3D4 domain-inserted antibody MDB1 Fab in complex with Plasmodium RIFIN (PF3D7_1373400) V2 domain
Map dataPrimary sharpened map
Sample
  • Complex: MDB1 Fab
    • Complex: MDB1 Fab in complex with RIFIN
      • Protein or peptide: MDB1 Fab heavy chain
      • Protein or peptide: MDB1 Fab light chain
      • Protein or peptide: Rifin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsLILRB1 / RIFIN / Malaria / Receptor-inserted antibody / MDB1 / IMMUNE SYSTEM
Function / homologyVariant surface antigen Rifin / Rifin / Rifin
Function and homology information
Biological speciesHomo sapiens (human) / Plasmodium falciparum (isolate 3D7) (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.54 Å
AuthorsXu K / Kwong PD
Funding support United States, 2 items
OrganizationGrant numberCountry
Other privateSimons Foundation SF349247 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)U24 GM129539 United States
CitationJournal: Nature / Year: 2021
Title: Structural basis of malaria RIFIN binding by LILRB1-containing antibodies.
Authors: Yiwei Chen / Kai Xu / Luca Piccoli / Mathilde Foglierini / Joshua Tan / Wenjie Jin / Jason Gorman / Yaroslav Tsybovsky / Baoshan Zhang / Boubacar Traore / Chiara Silacci-Fregni / Claudia ...Authors: Yiwei Chen / Kai Xu / Luca Piccoli / Mathilde Foglierini / Joshua Tan / Wenjie Jin / Jason Gorman / Yaroslav Tsybovsky / Baoshan Zhang / Boubacar Traore / Chiara Silacci-Fregni / Claudia Daubenberger / Peter D Crompton / Roger Geiger / Federica Sallusto / Peter D Kwong / Antonio Lanzavecchia /
Abstract: Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)-variant surface antigens that are expressed on infected erythrocytes-bind to the inhibitory receptor LAIR1, and ...Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)-variant surface antigens that are expressed on infected erythrocytes-bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to β2 microglobulin and RIFINs through their apical domains. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable-constant (VH-CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN-LILRB1 D3 interaction that is similar to that of RIFIN-LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH-CH1 elbow without affecting VH-VL or CH1-CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH-CH1 elbow.
History
DepositionOct 21, 2020-
Header (metadata) releaseMar 31, 2021-
Map releaseMar 31, 2021-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.65
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.65
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7khf
  • Surface level: 0.65
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22879.png

Downloads & links

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Map

FileDownload / File: emd_22879.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPrimary sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 320 pix.
= 346.56 Å		1.08 Å/pix.
x 320 pix.
= 346.56 Å		1.08 Å/pix.
x 320 pix.
= 346.56 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.083 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.65 / Movie #1: 0.65
Minimum - Maximum-2.0738816 - 3.5863357
Average (Standard dev.)-0.0027429024 (±0.080726914)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 346.56 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0831.0831.083
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z346.560346.560346.560
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-2.0743.586-0.003

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Supplemental data

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Mask #1

Fileemd_22879_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened map

Fileemd_22879_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_22879_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_22879_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : MDB1 Fab

EntireName: MDB1 Fab
Components
  • Complex: MDB1 Fab
    • Complex: MDB1 Fab in complex with RIFIN
      • Protein or peptide: MDB1 Fab heavy chain
      • Protein or peptide: MDB1 Fab light chain
      • Protein or peptide: Rifin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: MDB1 Fab

SupramoleculeName: MDB1 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: MDB1 Fab in complex with RIFIN

SupramoleculeName: MDB1 Fab in complex with RIFIN / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: MDB1 Fab heavy chain

MacromoleculeName: MDB1 Fab heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.384973 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QITLKESGPT LVERTQTLTL TCTFSGFSLT TDGLGVGWIR QPPGKALEWL ALIYYDDVRR YRPSLKSRLT ITKDTSKNRV VLTVTDMDP VDAGTYFCVH ASLFNLGSRN VYFRYWGQGT LVSVSSGVSK KPSLSVQPGP IVAPEETLTL QCGSDAGYNR F VLYKDGER ...String:
QITLKESGPT LVERTQTLTL TCTFSGFSLT TDGLGVGWIR QPPGKALEWL ALIYYDDVRR YRPSLKSRLT ITKDTSKNRV VLTVTDMDP VDAGTYFCVH ASLFNLGSRN VYFRYWGQGT LVSVSSGVSK KPSLSVQPGP IVAPEETLTL QCGSDAGYNR F VLYKDGER DFLQLAGAQP QAGLSQANFT LGPVSRSYGG QYRCYGAHNL SSEWSAPSDP LDILIAGQFY DRVSLSVQPG PT VASGENV TLLCQSQGWM QTFLLTKEGA ADDPWRLRST YQSQKYQAEF PMGPVTSAHA GTYRCYGSQS SKPYLLTHPS DPL ELVVSA STKGPSVFPL APCSRSTSES TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSS LGTKT YTCNVDHKPS NTKVDKRVES KY

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Macromolecule #2: MDB1 Fab light chain

MacromoleculeName: MDB1 Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.870232 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SYDLTQPPSV SVSPGQTARI TCSGDSLARQ FASWYQQKPG QSPVLLIYKN IERLSAIPER FSGSTSGTSV TLTISGVQAE DEADYFCQS ADDSGSYSLF GTGTRVSVLG QPKANPTVTL FPPSSEELQA NKATLVCLIS DFYPGAVTVA WKADGSPVKA G VETTKPSK ...String:
SYDLTQPPSV SVSPGQTARI TCSGDSLARQ FASWYQQKPG QSPVLLIYKN IERLSAIPER FSGSTSGTSV TLTISGVQAE DEADYFCQS ADDSGSYSLF GTGTRVSVLG QPKANPTVTL FPPSSEELQA NKATLVCLIS DFYPGAVTVA WKADGSPVKA G VETTKPSK QSNNKYAASS YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS

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Macromolecule #3: Rifin

MacromoleculeName: Rifin / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum (isolate 3D7) (eukaryote) / Strain: isolate 3D7
Molecular weightTheoretical: 15.420644 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
KELAEKAGAL AGEAARIPAA IDAVIEGIKS KFSIDTLGGE ALKSVIDGTN YYDASYITTA IYNKFQVSSC LPSVPFLGGP PVPGAGANK PICSAVDKLY LGSGNFLDKS SLPGSIQKDV AKIVAGAEQA AKAKAAMVAS DKTLAVETAK KQ

UniProtKB: Rifin

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration1 mg/mL
BufferpH: 7.4 / Component - Formula: PBS
GridModel: C-flat-1.2/1.3 / Material: COPPER / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 6473 / Average exposure time: 2.0 sec. / Average electron dose: 70.72 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 6010700
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 390908
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.15)
Final 3D classificationSoftware - Name: cryoSPARC

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Atomic model buiding 1

Initial modelPDB ID:

4lla


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7khf:
CryoEM structure of LILRB1 D3D4 domain-inserted antibody MDB1 Fab in complex with Plasmodium RIFIN (PF3D7_1373400) V2 domain

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