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- PDB-7o9s: Hantaan virus Gn in complex with Fab nnHTN-Gn2 -

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Basic information

Entry
Database: PDB / ID: 7o9s
TitleHantaan virus Gn in complex with Fab nnHTN-Gn2
Components
  • Envelope polyprotein
  • Fab nnHTN-Gn2 Heavy chain
  • Fab nnHTN-Gn2 Light chain
KeywordsVIRAL PROTEIN / Hantaan virus glycoprotein / Gn glycoprotein / Gn in complex with Fab / neutralizing antibody / viral glycoprotein in complex with antibody
Function / homology
Function and homology information


: / symbiont-mediated suppression of host TRAF-mediated signal transduction / host cell Golgi membrane / host cell mitochondrion / host cell surface / host cell endoplasmic reticulum membrane / virion membrane / signal transduction / membrane / metal ion binding
Similarity search - Function
: / Hantavirus glycoprotein Gn, base / Hantavirus glycoprotein Gn / ITAM motif, hantavirus type / Envelope glycoprotein precursor, Hantavirus / Hantavirus glycoprotein Gn, head / Hantavirus ITAM motif / ITAM motif hantavirus type profile. / : / Hantavirus glycoprotein Gc, C-terminal ...: / Hantavirus glycoprotein Gn, base / Hantavirus glycoprotein Gn / ITAM motif, hantavirus type / Envelope glycoprotein precursor, Hantavirus / Hantavirus glycoprotein Gn, head / Hantavirus ITAM motif / ITAM motif hantavirus type profile. / : / Hantavirus glycoprotein Gc, C-terminal / Hantavirus glycoprotein Gc / Hantavirus glycoprotein Gc, N-terminal
Similarity search - Domain/homology
Envelopment polyprotein
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
Hantaan orthohantavirus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsRissanen, I. / Bowden, T.A. / Huiskonen, J.T. / Stass, R.
Funding support United Kingdom, Finland, United States, 11items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/L009528/1 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/S007555/1 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/N002091/1 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/K024426/1 United Kingdom
Medical Research Council (MRC, United Kingdom)MC/PC/15068 United Kingdom
Academy of Finland309605 Finland
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R41AI132047 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R41AI132047-01S1 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R43AI142911 United States
Wellcome Trust203141/Z/16/Z United Kingdom
Wellcome Trust093305/Z/10/Z United Kingdom
CitationJournal: mBio / Year: 2021
Title: Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen.
Authors: Ilona Rissanen / Stefanie A Krumm / Robert Stass / Annalis Whitaker / James E Voss / Emily A Bruce / Sylvia Rothenberger / Stefan Kunz / Dennis R Burton / Juha T Huiskonen / Jason W Botten / ...Authors: Ilona Rissanen / Stefanie A Krumm / Robert Stass / Annalis Whitaker / James E Voss / Emily A Bruce / Sylvia Rothenberger / Stefan Kunz / Dennis R Burton / Juha T Huiskonen / Jason W Botten / Thomas A Bowden / Katie J Doores /
Abstract: Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two ...Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two glycoproteins, Gn and Gc, which are responsible for negotiating host cell entry and constitute key therapeutic targets. Here, we demonstrate that recombinantly derived Gn from Hantaan virus (HTNV) elicits a neutralizing antibody response (serum dilution that inhibits 50% infection [ID], 1:200 to 1:850) in an animal model. Using antigen-specific B cell sorting, we isolated monoclonal antibodies (mAbs) exhibiting neutralizing and non-neutralizing activity, termed mAb HTN-Gn1 and mAb nnHTN-Gn2, respectively. Crystallographic analysis reveals that these mAbs target spatially distinct epitopes at disparate sites of the N-terminal region of the HTNV Gn ectodomain. Epitope mapping onto a model of the higher order (Gn-Gc) spike supports the immune accessibility of the mAb HTN-Gn1 epitope, a hypothesis confirmed by electron cryo-tomography of the antibody with virus-like particles. These data define natively exposed regions of the hantaviral Gn that can be targeted in immunogen design. The spillover of pathogenic hantaviruses from rodent reservoirs into the human population poses a continued threat to human health. Here, we show that a recombinant form of the Hantaan virus (HTNV) surface-displayed glycoprotein, Gn, elicits a neutralizing antibody response in rabbits. We isolated a neutralizing (HTN-Gn1) and a non-neutralizing (nnHTN-Gn2) monoclonal antibody and provide the first molecular-level insights into how the Gn glycoprotein may be targeted by the antibody-mediated immune response. These findings may guide rational vaccine design approaches focused on targeting the hantavirus glycoprotein envelope.
History
DepositionApr 16, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 15, 2021Group: Database references / Category: citation / database_2
Item: _citation.journal_volume / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Fab nnHTN-Gn2 Heavy chain
L: Fab nnHTN-Gn2 Light chain
A: Envelope polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,9748
Polymers87,2553
Non-polymers7195
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7040 Å2
ΔGint-28 kcal/mol
Surface area32870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.130, 76.900, 174.360
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Antibody Fab nnHTN-Gn2 Heavy chain


Mass: 24296.213 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Plasmid: pHLsec / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
#2: Antibody Fab nnHTN-Gn2 Light chain


Mass: 22607.914 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Plasmid: pHLsec / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
#3: Protein Envelope polyprotein / M polyprotein


Mass: 40350.871 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hantaan orthohantavirus / Plasmid: pHLsec / Cell line (production host): HEK293T / Production host: Homo sapiens (human) / References: UniProt: A0A077D153
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: 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.: 2 / Source method: obtained synthetically / 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
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.92 Å3/Da / Density % sol: 57.94 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M sodium cacodylate pH 6.5, 5 % w/v PGA-LM and 20 % w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9686 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 13, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 2.7→76.13 Å / Num. obs: 28789 / % possible obs: 99.7 % / Redundancy: 13.1 % / Biso Wilson estimate: 61.58 Å2 / Rpim(I) all: 0.023 / Rrim(I) all: 0.084 / Net I/σ(I): 19.8 / Num. measured all: 377959
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) all% possible all
2.7-2.7513.43.413970.2060.75999.1
7.33-76.11248.215990.0110.039100

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Processing

Software
NameVersionClassification
PHENIX1.19refinement
xia2data scaling
PDB_EXTRACT3.27data extraction
xia2data reduction
PHENIX1.19phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5OPG, 5DRN

5opg

5drn


Resolution: 2.7→51.67 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 32.94 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2669 1409 4.91 %
Rwork0.2106 27289 -
obs0.2132 28698 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 201.57 Å2 / Biso mean: 82.979 Å2 / Biso min: 44.09 Å2
Refinement stepCycle: final / Resolution: 2.7→51.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5808 0 46 0 5854
Biso mean--100.56 --
Num. residues----770
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7-2.80.37371300.30382655278599
2.8-2.910.39931600.27822658281899
2.91-3.040.36721290.27612690281999
3.04-3.20.35071510.26342682283399
3.2-3.40.34431530.24392679283299
3.4-3.660.26141550.2252706286199
3.66-4.030.26061580.218327102868100
4.03-4.620.19771170.178227662883100
4.62-5.810.2159970.167328392936100
5.82-51.670.23521590.197229043063100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.30430.0914-0.73732.3437-1.05136.52350.0730.05130.0855-0.0575-0.10070.19990.066-0.7154-0.02620.37110.1086-0.00360.8502-0.04710.3758-57.2223.75732.965
21.3795-2.45540.30097.5886-0.23011.66480.63770.66810.0353-1.154-0.0389-0.70020.2080.3037-0.01590.41550.1042-0.03221.4429-0.03830.6129-42.69918.147-3.571
34.5716-2.2635-1.09294.22-0.93352.1697-0.34140.1724-1.00130.18140.01760.79410.4895-0.14670.15130.35260.00640.02761.13730.0340.5649-49.06614.1958.054
45.3741-3.4353-1.49725.2077-1.28872.0546-0.05580.6047-0.6211-0.07110.00450.33320.1017-0.5840.07580.3810.0498-0.00591.24840.01270.4403-50.10418.5943.038
58.0508-6.4336-4.42088.75844.33465.05470.0124-0.75690.3070.05370.3097-0.8498-0.1221.9079-0.21610.55580.0787-0.0241.39250.04020.4659-31.319.58536.137
63.18110.657-0.67323.84813.0556.1029-0.0138-0.06740.1562-0.0748-0.15970.036-0.11450.50420.18710.52880.1711-0.03710.96640.04480.3967-42.19315.95937.069
72.64070.0807-1.15272.99523.62855.0229-0.2493-0.9177-0.57610.96510.3275-0.60720.56220.99790.04520.81590.3087-0.05141.06420.08770.4765-37.8498.16341.117
81.44710.7825-0.65971.55591.6594.3638-0.1111-0.6129-0.12380.08810.0169-0.04220.17190.5327-0.01120.49550.1452-0.05051.0890.05170.4334-39.0418.32537.771
91.12830.7555-1.56450.5159-1.08382.36670.2193-0.4063-0.3472-0.1353-0.037-0.37280.41690.8817-0.25040.49330.42220.00921.3574-0.0360.5503-27.9213.91619.632
107.2114-1.04020.99514.4110.69561.4669-0.41310.69870.4313-0.29650.27130.5612-0.2019-0.3447-0.42550.44560.04680.01191.70420.17020.4661-41.88324.742-4.668
117.0306-3.57722.42254.7064-2.10933.6663-0.2239-0.0330.30460.1050.2776-0.36140.03690.0694-0.00430.34540.04990.02661.2572-0.01780.595-32.35523.315.265
126.5968-2.07671.21475.4505-3.55524.6064-0.2294-0.19690.6764-0.00780.43790.2147-0.084-0.2458-0.26510.41830.0227-0.0390.9118-0.12120.4779-33.70823.3619.617
132.77981.0675-1.13550.5581-0.07111.9425-0.09061.21430.8062-0.31670.30150.1695-0.376-0.7011-0.92060.49710.1140.07711.79720.28490.5931-38.13230.0080.083
143.0353-1.62310.97151.9254-0.50982.0454-0.10280.64911.5083-0.20880.28970.0305-0.10.47110.25130.4714-0.14620.01181.74820.29660.9427-28.75927.359-2.117
155.45670.4765-1.20397.2528-0.32290.27390.09110.61780.2815-1.26170.31550.40430.5046-0.3504-0.47070.5436-0.0960.10541.78180.06750.4822-29.05923.569-4.98
164.0045-1.3258-2.52293.8999-0.91765.1246-0.10970.1495-0.09130.2501-0.11670.71760.4846-0.64430.12940.5368-0.02650.02371.255-0.0210.5439-65.02922.31361.657
172.9925-0.4911-0.55213.12550.98383.4313-0.17120.28230.6053-0.20190.1283-0.2148-0.01730.6074-0.0190.49690.08710.00350.99340.02570.4888-45.9628.463.288
182.9553-2.96061.20117.3792-1.63933.7717-0.2267-0.7577-0.2385-0.21860.7607-1.02840.81380.2786-0.52380.67250.0628-0.04941.60150.00160.7791-32.07318.29573.285
192.02212.3454-0.93344.4899-0.19714.9058-0.32510.46450.62650.41990.63320.8049-0.4931-0.0613-0.36640.54640.10440.02861.06010.10340.5364-56.77733.2267.387
203.6029-0.0771-1.06972.35470.72984.32450.1880.75880.7445-0.1501-0.15090.0577-0.0121-0.56680.02810.6360.0990.07071.1770.02930.4074-61.79525.10858.885
215.76351.8946-2.01543.95210.42689.64520.20160.7890.7862-0.18370.31170.13530.584-1.42430.13420.6775-0.17270.04481.2211-0.02760.7292-80.46822.13777.158
223.51411.9259-1.63932.1312-0.30533.78090.3315-0.47780.47720.51390.01940.00510.48310.3118-0.15750.58210.0530.110.90140.03460.505-59.50731.91984.01
235.93323.8894-2.55038.2807-1.70514.82040.2372-0.71950.2301-0.1177-0.19350.14880.2656-0.784-0.00280.38650.05950.07540.7062-0.05660.3522-59.91331.00685.346
242.5793-3.1485-0.04823.88060.70684.6903-0.19790.0907-0.2908-0.22910.1682-0.24950.6381.44070.02280.60380.1465-0.01411.25070.01120.407-41.27720.40779.502
255.7106-0.2276-1.32511.28090.02322.66060.2627-0.3567-0.2930.3749-0.2502-0.06780.64370.0645-0.01740.6159-0.00250.07220.9929-0.00370.3712-52.61526.09481.111
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN H AND RESID 0:123 )H0 - 123
2X-RAY DIFFRACTION2( CHAIN H AND RESID 124:149 )H124 - 149
3X-RAY DIFFRACTION3( CHAIN H AND RESID 150:171 )H150 - 171
4X-RAY DIFFRACTION4( CHAIN H AND RESID 172:215 )H172 - 215
5X-RAY DIFFRACTION5( CHAIN L AND RESID 0:24 )L0 - 24
6X-RAY DIFFRACTION6( CHAIN L AND RESID 25:47 )L25 - 47
7X-RAY DIFFRACTION7( CHAIN L AND RESID 48:68 )L48 - 68
8X-RAY DIFFRACTION8( CHAIN L AND RESID 69:103 )L69 - 103
9X-RAY DIFFRACTION9( CHAIN L AND RESID 104:115 )L104 - 115
10X-RAY DIFFRACTION10( CHAIN L AND RESID 116:130 )L116 - 130
11X-RAY DIFFRACTION11( CHAIN L AND RESID 131:151 )L131 - 151
12X-RAY DIFFRACTION12( CHAIN L AND RESID 152:173 )L152 - 173
13X-RAY DIFFRACTION13( CHAIN L AND RESID 174:189 )L174 - 189
14X-RAY DIFFRACTION14( CHAIN L AND RESID 190:199 )L190 - 199
15X-RAY DIFFRACTION15( CHAIN L AND RESID 200:213 )L200 - 213
16X-RAY DIFFRACTION16( CHAIN A AND RESID 18:45 )A18 - 45
17X-RAY DIFFRACTION17( CHAIN A AND RESID 46:85 )A46 - 85
18X-RAY DIFFRACTION18( CHAIN A AND RESID 86:106 )A86 - 106
19X-RAY DIFFRACTION19( CHAIN A AND RESID 107:136 )A107 - 136
20X-RAY DIFFRACTION20( CHAIN A AND RESID 137:172 )A137 - 172
21X-RAY DIFFRACTION21( CHAIN A AND RESID 173:201 )A173 - 201
22X-RAY DIFFRACTION22( CHAIN A AND RESID 202:229 )A202 - 229
23X-RAY DIFFRACTION23( CHAIN A AND RESID 230:275 )A230 - 275
24X-RAY DIFFRACTION24( CHAIN A AND RESID 276:324 )A276 - 324
25X-RAY DIFFRACTION25( CHAIN A AND RESID 325:371 )A325 - 371

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