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TitleTailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens.
Journal, issue, pagesElife, Vol. 9, Year 2020
Publish dateAug 4, 2020
AuthorsGeorge Ueda / Aleksandar Antanasijevic / Jorge A Fallas / William Sheffler / Jeffrey Copps / Daniel Ellis / Geoffrey B Hutchinson / Adam Moyer / Anila Yasmeen / Yaroslav Tsybovsky / Young-Jun Park / Matthew J Bick / Banumathi Sankaran / Rebecca A Gillespie / Philip Jm Brouwer / Peter H Zwart / David Veesler / Masaru Kanekiyo / Barney S Graham / Rogier W Sanders / John P Moore / Per Johan Klasse / Andrew B Ward / Neil P King / David Baker /
PubMed AbstractMultivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self- ...Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.
External linksElife / PubMed:32748788 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.303 - 34.17 Å
Structure data

EMDB-21162:
De novo designed tetrahedral nanoparticle T33_dn2
Method: EM (single particle) / Resolution: 17.11 Å

EMDB-21163:
De novo designed tetrahedral nanoparticle T33_dn5
Method: EM (single particle) / Resolution: 19.68 Å

EMDB-21164:
De novo designed tetrahedral nanoparticle T33_dn10
Method: EM (single particle) / Resolution: 19.13 Å

EMDB-21165:
De novo designed octahedral nanoparticle O43_dn18
Method: EM (single particle) / Resolution: 16.4 Å

EMDB-21166:
De novo designed icosahedral nanoparticle I53_dn5
Method: EM (single particle) / Resolution: 18.74 Å

EMDB-21167:
BG505-SOSIP-T33_dn2A nanoparticle fusion component
Method: EM (single particle) / Resolution: 15.62 Å

EMDB-21168:
BG505-SOSIP-T33_dn2A nanoparticle fusion component in complex with VRC01-Fab
Method: EM (single particle) / Resolution: 15.62 Å

EMDB-21169:
De novo designed tetrahedral nanoparticle T33_dn2 presenting BG505-SOSIP
Method: EM (single particle) / Resolution: 34.17 Å

EMDB-21170:
Tetrahedral nanoparticle T33_dn10 presenting BG505-SOSIP
Method: EM (single particle) / Resolution: 25.67 Å

EMDB-21171:
Icosahedral Nanoparticle I53_dn5 presenting BG505-SOSIP
Method: EM (single particle) / Resolution: 23.48 Å

EMDB-21172, PDB-6vfh:
De novo designed tetrahedral nanoparticle T33_dn10
Method: EM (single particle) / Resolution: 3.86 Å

EMDB-21173, PDB-6vfi:
De novo designed octahedral nanoparticle O43_dn18
Method: EM (single particle) / Resolution: 4.54 Å

EMDB-21174, PDB-6vfj:
De novo designed icosahedral nanoparticle I53_dn5
Method: EM (single particle) / Resolution: 5.35 Å

PDB-6v8e:
Computationally designed C3-symmetric homotrimer from TPR repeat protein
Method: X-RAY DIFFRACTION / Resolution: 2.53 Å

PDB-6veh:
Computationally designed C3-symmetric homotrimer from HEAT repeat protein
Method: X-RAY DIFFRACTION / Resolution: 2.303 Å

Chemicals

ChemComp-HOH:
WATER / Water

Source
  • synthetic construct (others)
KeywordsDE NOVO PROTEIN / designed trimers / designed nanoparticles / ribosome-binding site / designed protein / vaccine / De novo / Nanoparticle

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