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- PDB-6xgc: CryoEM structure of influenza hemagglutinin A/Michigan/45/2015 in... -

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Basic information

Entry
Database: PDB / ID: 6xgc
TitleCryoEM structure of influenza hemagglutinin A/Michigan/45/2015 in complex with cyno antibody 1C4
Components
  • (Hemagglutinin ...) x 2
  • 1C4 Fab heavy chain
  • 1C4 Fab light chain
KeywordsANTIVIRAL PROTEIN / influenza / hemagglutinin / antibody / vaccine / broadly neutralizing antibody
Function / homology
Function and homology information


viral budding from plasma membrane / clathrin-dependent endocytosis of virus by host cell / membrane => GO:0016020 / host cell surface receptor binding / apical plasma membrane / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane
Similarity search - Function
Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein
Similarity search - Domain/homology
Hemagglutinin / Hemagglutinin
Similarity search - Component
Biological speciesInfluenza A virus
Macaca fascicularis (crab-eating macaque)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsQiu, Y. / Zhou, Y.
CitationJournal: Sci Transl Med / Year: 2021
Title: Broad neutralization of H1 and H3 viruses by adjuvanted influenza HA stem vaccines in nonhuman primates.
Authors: Nicole Darricarrère / Yu Qiu / Masaru Kanekiyo / Adrian Creanga / Rebecca A Gillespie / Syed M Moin / Jacqueline Saleh / Jose Sancho / Te-Hui Chou / Yanfeng Zhou / Ruijun Zhang / Shujia Dai ...Authors: Nicole Darricarrère / Yu Qiu / Masaru Kanekiyo / Adrian Creanga / Rebecca A Gillespie / Syed M Moin / Jacqueline Saleh / Jose Sancho / Te-Hui Chou / Yanfeng Zhou / Ruijun Zhang / Shujia Dai / Anthony Moody / Kevin O Saunders / Michelle C Crank / John R Mascola / Barney S Graham / Chih-Jen Wei / Gary J Nabel /
Abstract: Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most ...Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus-associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.
History
DepositionJun 17, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 10, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 17, 2021Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

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Assembly

Deposited unit
A: Hemagglutinin HA1 chain
B: Hemagglutinin HA2 chain
M: 1C4 Fab heavy chain
N: 1C4 Fab light chain
C: Hemagglutinin HA1 chain
D: Hemagglutinin HA2 chain
H: 1C4 Fab heavy chain
L: 1C4 Fab light chain
E: Hemagglutinin HA1 chain
F: Hemagglutinin HA2 chain
I: 1C4 Fab heavy chain
J: 1C4 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)334,54830
Polymers329,95712
Non-polymers4,59118
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Hemagglutinin ... , 2 types, 6 molecules ACEBDF

#1: Protein Hemagglutinin HA1 chain


Mass: 36432.949 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus (A/Michigan/45/2015(H1N1))
Strain: A/Michigan/45/2015(H1N1) / Gene: HA / Production host: Homo sapiens (human) / References: UniProt: A0A3Q8LWJ2
#2: Protein Hemagglutinin HA2 chain


Mass: 25109.902 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus (A/Michigan/45/2015(H1N1))
Strain: A/Michigan/45/2015(H1N1) / Gene: HA / Production host: Homo sapiens (human) / References: UniProt: A0A482NTT4

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Antibody , 2 types, 6 molecules MHINLJ

#3: Antibody 1C4 Fab heavy chain


Mass: 25605.572 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca fascicularis (crab-eating macaque)
Production host: Homo sapiens (human)
#4: Antibody 1C4 Fab light chain


Mass: 22837.086 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca fascicularis (crab-eating macaque)
Production host: Homo sapiens (human)

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Sugars , 2 types, 18 molecules

#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 15
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1A/Michigan/45/2015(H1N1) hemagglutinin in complex with 1C4 FabCOMPLEX#1-#40MULTIPLE SOURCES
2HemagglutininCOMPLEX#1-#21RECOMBINANT
31C4 FabCOMPLEX#3-#41RECOMBINANT
Molecular weightValue: 320 kDa/nm / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Influenza A virus (A/Michigan/45/2015(H1N1))1777792
23Macaca fascicularis (crab-eating macaque)9541
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Buffer solutionpH: 8.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 449762 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00117427
ELECTRON MICROSCOPYf_angle_d0.38223631
ELECTRON MICROSCOPYf_dihedral_angle_d7.7826303
ELECTRON MICROSCOPYf_chiral_restr0.0382625
ELECTRON MICROSCOPYf_plane_restr0.0033030

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