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- EMDB-9135: Cryo-EM structure of Human Parainfluenza Virus Type 3 (hPIV3) in ... -

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Basic information

Entry
Database: EMDB / ID: EMD-9135
TitleCryo-EM structure of Human Parainfluenza Virus Type 3 (hPIV3) in complex with antibody PIA174
Map data
Sample
  • Complex: Complex of hPIV3 Env Q162C-L168C, I213C-G230C, A463V, I474Y in complex with antibody PIA174
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: PIA174 Fab Heavy chain
    • Protein or peptide: PIA174 Fab Light chain
Function / homologyPrecursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0 / membrane => GO:0016020 / fusion of virus membrane with host plasma membrane / viral envelope / host cell plasma membrane / virion membrane / plasma membrane / Fusion glycoprotein F0
Function and homology information
Biological speciesHuman respirovirus 3 / Human parainfluenza virus 3 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsAcharya P / Stewart-Jones G / Carragher B / Potter CS / Kwong PD
CitationJournal: Proc Natl Acad Sci U S A / Year: 2018
Title: Structure-based design of a quadrivalent fusion glycoprotein vaccine for human parainfluenza virus types 1-4.
Authors: Guillaume B E Stewart-Jones / Gwo-Yu Chuang / Kai Xu / Tongqing Zhou / Priyamvada Acharya / Yaroslav Tsybovsky / Li Ou / Baoshan Zhang / Blanca Fernandez-Rodriguez / Valentina Gilardi / ...Authors: Guillaume B E Stewart-Jones / Gwo-Yu Chuang / Kai Xu / Tongqing Zhou / Priyamvada Acharya / Yaroslav Tsybovsky / Li Ou / Baoshan Zhang / Blanca Fernandez-Rodriguez / Valentina Gilardi / Chiara Silacci-Fregni / Martina Beltramello / Ulrich Baxa / Aliaksandr Druz / Wing-Pui Kong / Paul V Thomas / Yongping Yang / Kathryn E Foulds / John-Paul Todd / Hui Wei / Andres M Salazar / Diana G Scorpio / Bridget Carragher / Clinton S Potter / Davide Corti / John R Mascola / Antonio Lanzavecchia / Peter D Kwong /
Abstract: Parainfluenza virus types 1-4 (PIV1-4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised ...Parainfluenza virus types 1-4 (PIV1-4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised individuals. To obtain a vaccine effective against all four PIV types, we engineered mutations in each of the four PIV fusion (F) glycoproteins to stabilize their metastable prefusion states, as such stabilization had previously enabled the elicitation of high-titer neutralizing antibodies against the related respiratory syncytial virus. A cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, bound to the prefusion-specific antibody PIA174, revealed atomic-level details for how introduced mutations improved stability as well as how a single PIA174 antibody recognized the trimeric apex of prefusion PIV3 F. Nine combinations of six newly identified disulfides and two cavity-filling mutations stabilized the prefusion PIV3 F immunogens and induced 200- to 500-fold higher neutralizing titers in mice than were elicited by PIV3 F in the postfusion conformation. For PIV1, PIV2, and PIV4, we also obtained stabilized prefusion Fs, for which prefusion versus postfusion titers were 2- to 20-fold higher. Elicited murine responses were PIV type-specific, with little cross-neutralization of other PIVs. In nonhuman primates (NHPs), quadrivalent immunization with prefusion-stabilized Fs from PIV1-4 consistently induced potent neutralizing responses against all four PIVs. For PIV3, the average elicited NHP titer from the quadrivalent immunization was more than fivefold higher than any titer observed in a cohort of over 100 human adults, highlighting the ability of a prefusion-stabilized immunogen to elicit especially potent neutralization.
History
DepositionSep 24, 2018-
Header (metadata) releaseOct 31, 2018-
Map releaseNov 14, 2018-
UpdateDec 18, 2019-
Current statusDec 18, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.67
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 1.67
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6mjz
  • Surface level: 1.67
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9135.png

Downloads & links

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Map

FileDownload / File: emd_9135.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 1.67 / Movie #1: 1.67
Minimum - Maximum-2.4087799 - 6.054476
Average (Standard dev.)0.007259601 (±0.10983016)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 352.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.11.11.1
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z352.000352.000352.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-2.4096.0540.007

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Supplemental data

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Sample components

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Entire : Complex of hPIV3 Env Q162C-L168C, I213C-G230C, A463V, I474Y in co...

EntireName: Complex of hPIV3 Env Q162C-L168C, I213C-G230C, A463V, I474Y in complex with antibody PIA174
Components
  • Complex: Complex of hPIV3 Env Q162C-L168C, I213C-G230C, A463V, I474Y in complex with antibody PIA174
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: PIA174 Fab Heavy chain
    • Protein or peptide: PIA174 Fab Light chain

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Supramolecule #1: Complex of hPIV3 Env Q162C-L168C, I213C-G230C, A463V, I474Y in co...

SupramoleculeName: Complex of hPIV3 Env Q162C-L168C, I213C-G230C, A463V, I474Y in complex with antibody PIA174
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Human respirovirus 3

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Macromolecule #1: Fusion glycoprotein F0

MacromoleculeName: Fusion glycoprotein F0 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human parainfluenza virus 3
Molecular weightTheoretical: 54.970625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QIDITKLQHV GVLVNSPKGM KISQNFETRY LILSLIPKIE DSNSCGDQQI KQYKRLLDRL IIPLYDGLKL QKDVIVTNQE SNENTDPRT ERFFGGVIGT IALGVATSAQ ITAAVALVEA KQAKSDIEKL KEAIRDTNKA VQSVCSSVGN CIVAIKSVQD Y VNKEIVPS ...String:
QIDITKLQHV GVLVNSPKGM KISQNFETRY LILSLIPKIE DSNSCGDQQI KQYKRLLDRL IIPLYDGLKL QKDVIVTNQE SNENTDPRT ERFFGGVIGT IALGVATSAQ ITAAVALVEA KQAKSDIEKL KEAIRDTNKA VQSVCSSVGN CIVAIKSVQD Y VNKEIVPS IARLGCEAAG LQLGIALTQH YSELTNCFGD NIGSLQEKGI KLQCIASLYR TNITEIFTTS TVDKYDIYDL LF TESIKVR VIDVDLNDYS ITLQVRLPLL TRLLNTQIYK VDSISYNIQN REWYIPLPSH IMTKGAFLGG ADVKECIEAF SSY ICPSDP GFVLNHEMES CLSGNISQCP RTTVTSDIVP RYAFVNGGVV ANCITTTCTC NGIGNRINQP PDQGVKIITH KECN TIGIN GMLFNTNKEG TLAFYTPDDI TLNNSVALDP IDISIELNKV KSDLEESKEW YRRSNQKLSA IEDKIEEILS KIYHI ENEI ARIKKLIGEA P

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Macromolecule #2: PIA174 Fab Heavy chain

MacromoleculeName: PIA174 Fab Heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.512453 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VQLQESGPGL VKPSETLSLT CTVSGGSVSS YYWSWIRQPP GKGLEWIGNI YYSGTTKYNP SLKSRVTISV DVSKNQFSLN LISVTAADT AVYFCARQVK SGWFVQPFDY WGQGALVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
VQLQESGPGL VKPSETLSLT CTVSGGSVSS YYWSWIRQPP GKGLEWIGNI YYSGTTKYNP SLKSRVTISV DVSKNQFSLN LISVTAADT AVYFCARQVK SGWFVQPFDY WGQGALVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPK

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Macromolecule #3: PIA174 Fab Light chain

MacromoleculeName: PIA174 Fab Light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.68624 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QMTQSPPSLS AYVGDRVTIT CRASQAIANY LAWFQQKPGK APKSLIYAAS TLQSGVPSRF SGSGSGTDFT LTISSLQPED FATYYCHQY NTYPITFGQG TRLEIKRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK ...String:
QMTQSPPSLS AYVGDRVTIT CRASQAIANY LAWFQQKPGK APKSLIYAAS TLQSGVPSRF SGSGSGTDFT LTISSLQPED FATYYCHQY NTYPITFGQG TRLEIKRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKS

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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: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 95 %

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Electron microscopy

MicroscopeFEI TITAN
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 1.4 e/Å2

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Image processing

CTF correctionSoftware - Name: Gctf
Startup modelType of model: OTHER / Details: Ab initio model
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 4 / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 97177

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