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- PDB-5c0s: Crystal structure of a generation 4 influenza hemagglutinin stabi... -

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Basic information

Entry
Database: PDB / ID: 5c0s
TitleCrystal structure of a generation 4 influenza hemagglutinin stabilized stem in complex with the broadly neutralizing antibody CR6261
Components
  • CR6261 antibody heavy chain
  • CR6261 antibody light chain
  • Hemagglutinin, Envelope glycoprotein, Fibritin fusion protein
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Hemagglutinin / immunogen / trimer / complex / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


Synthesis and processing of ENV and VPU / evasion of host immune response / Alpha-defensins / Dectin-2 family / Binding and entry of HIV virion / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / host cell endosome membrane / viral budding from plasma membrane ...Synthesis and processing of ENV and VPU / evasion of host immune response / Alpha-defensins / Dectin-2 family / Binding and entry of HIV virion / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / host cell endosome membrane / viral budding from plasma membrane / actin filament organization / Assembly Of The HIV Virion / Budding and maturation of HIV virion / clathrin-dependent endocytosis of virus by host cell / viral protein processing / host cell surface receptor binding / symbiont entry into host cell / apical plasma membrane / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / structural molecule activity / virion membrane / membrane
Similarity search - Function
Fibritin C-terminal / Fibritin C-terminal region / Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein / Envelope glycoprotein Gp160 / Retroviral envelope protein / Retroviral envelope protein GP41-like ...Fibritin C-terminal / Fibritin C-terminal region / Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein / Envelope glycoprotein Gp160 / Retroviral envelope protein / Retroviral envelope protein GP41-like / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120
Similarity search - Domain/homology
Fibritin / Envelope glycoprotein gp160 / Hemagglutinin
Similarity search - Component
Biological speciesInfluenza A virus
Human immunodeficiency virus type 1 group M subtype B
Enterobacteria phage T4 (virus)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 4.3 Å
AuthorsBoyington, J.C. / Kwong, P.D. / Nabel, G.J. / Mascola, J.R.
CitationJournal: Nat Med / Year: 2015
Title: Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection.
Authors: Hadi M Yassine / Jeffrey C Boyington / Patrick M McTamney / Chih-Jen Wei / Masaru Kanekiyo / Wing-Pui Kong / John R Gallagher / Lingshu Wang / Yi Zhang / M Gordon Joyce / Daniel Lingwood / ...Authors: Hadi M Yassine / Jeffrey C Boyington / Patrick M McTamney / Chih-Jen Wei / Masaru Kanekiyo / Wing-Pui Kong / John R Gallagher / Lingshu Wang / Yi Zhang / M Gordon Joyce / Daniel Lingwood / Syed M Moin / Hanne Andersen / Yoshinobu Okuno / Srinivas S Rao / Audray K Harris / Peter D Kwong / John R Mascola / Gary J Nabel / Barney S Graham /
Abstract: The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of ...The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of influenza vaccines. In contrast, the immunogenically subdominant stem region of HA is highly conserved and recognized by antibodies capable of binding multiple HA subtypes. Here we report the structure-based development of an H1 HA stem-only immunogen that confers heterosubtypic protection in mice and ferrets. Six iterative cycles of structure-based design (Gen1-Gen6) yielded successive H1 HA stabilized-stem (HA-SS) immunogens that lack the immunodominant head domain. Antigenic characterization, determination of two HA-SS crystal structures in complex with stem-specific monoclonal antibodies and cryo-electron microscopy analysis of HA-SS on ferritin nanoparticles (H1-SS-np) confirmed the preservation of key structural elements. Vaccination of mice and ferrets with H1-SS-np elicited broadly cross-reactive antibodies that completely protected mice and partially protected ferrets against lethal heterosubtypic H5N1 influenza virus challenge despite the absence of detectable H5N1 neutralizing activity in vitro. Passive transfer of immunoglobulin from H1-SS-np-immunized mice to naive mice conferred protection against H5N1 challenge, indicating that vaccine-elicited HA stem-specific antibodies can protect against diverse group 1 influenza strains.
History
DepositionJun 12, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 16, 2015Group: Database references
Revision 1.2Oct 21, 2015Group: Source and taxonomy
Revision 1.3Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hemagglutinin, Envelope glycoprotein, Fibritin fusion protein
H: CR6261 antibody heavy chain
L: CR6261 antibody light chain


Theoretical massNumber of molelcules
Total (without water)81,4513
Polymers81,4513
Non-polymers00
Water00
1
A: Hemagglutinin, Envelope glycoprotein, Fibritin fusion protein
H: CR6261 antibody heavy chain
L: CR6261 antibody light chain

A: Hemagglutinin, Envelope glycoprotein, Fibritin fusion protein
H: CR6261 antibody heavy chain
L: CR6261 antibody light chain

A: Hemagglutinin, Envelope glycoprotein, Fibritin fusion protein
H: CR6261 antibody heavy chain
L: CR6261 antibody light chain


Theoretical massNumber of molelcules
Total (without water)244,3529
Polymers244,3529
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Unit cell
Length a, b, c (Å)101.649, 101.649, 186.022
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Hemagglutinin, Envelope glycoprotein, Fibritin fusion protein / Env polyprotein


Mass: 34211.746 Da / Num. of mol.: 1
Fragment: UNP Q6WG00 residues 18-49, 328-402, 436-517, UNP P04578 residues 546-577, 628-654 and UNP D9IEJ2 residues 458-485
Source method: isolated from a genetically manipulated source
Details: Engineered fusion between an influenza hemagglutinin stem, an HIV-1 gp41 six-helix bundle and T4 phage foldon
Source: (gene. exp.) Influenza A virus, Human immunodeficiency virus type 1 group M subtype B, Enterobacteria phage T4
Strain: A/New Caledonia/20/1999(H1N1), isolate HXB2 / Gene: HA, env, wac / Cell line (production host): HEK293 GNTI-/- / Organ (production host): Kidney / Production host: Homo sapiens (human)
References: UniProt: Q6WG00, UniProt: P04578, UniProt: D9IEJ2
#2: Antibody CR6261 antibody heavy chain


Mass: 23981.137 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Organ (production host): Kidney / Production host: Homo sapiens (human)
#3: Antibody CR6261 antibody light chain


Mass: 23257.783 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Organ (production host): Kidney / Production host: Homo sapiens (human)

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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: 2.27 Å3/Da / Density % sol: 45.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 7% (w/v) PEG 4000, 4.5% (v/v) isopropanol, 100 mM imidazole, pH 6.5
PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 7, 2012
RadiationMonochromator: SI 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 4.3→50 Å / Num. obs: 4799 / % possible obs: 99 % / Observed criterion σ(I): -3 / Redundancy: 3.9 % / Rmerge(I) obs: 0.154 / Net I/σ(I): 7.6
Reflection shellResolution: 4.3→4.45 Å / Redundancy: 3 % / Rmerge(I) obs: 0.563 / Mean I/σ(I) obs: 2.1 / % possible all: 96.9

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Processing

Software
NameVersionClassification
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
PHENIX1.8.2_1309refinement
Coot0.7model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1RU7 (5-36, 315-323 chain A, 514-559, 590-660 chain B), 1SZT (3-29, 42-67 chain A), 3GBM (chains H and L)

1ru7

1szt

3gbm


Resolution: 4.3→27.06 Å / SU ML: 0.65 / Cross valid method: FREE R-VALUE / σ(F): 1.45 / Phase error: 39.31 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.31 241 5.02 %Random selection
Rwork0.238 ---
obs0.241 4799 99 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 4.3→27.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5158 0 0 0 5158
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0055275
X-RAY DIFFRACTIONf_angle_d0.9827162
X-RAY DIFFRACTIONf_dihedral_angle_d15.1571905
X-RAY DIFFRACTIONf_chiral_restr0.062803
X-RAY DIFFRACTIONf_plane_restr0.004924
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
4.3027-5.41390.35981230.28912261X-RAY DIFFRACTION99
5.4139-27.06050.28811180.21662297X-RAY DIFFRACTION99
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)
10.0331-0.0283-0.03420.11160.07720.05310.06050.03740.17950.085-0.2739-0.2686-0.2452-0.2341-0.32820.6544-0.2688-0.1-0.75280.7462-0.6547-0.92221.0681-13.4547
20.3436-0.0202-0.1750.5484-0.18070.45920.0818-0.10510.20030.56230.1143-0.31380.28770.13490.07240.6402-0.2149-0.23950.4960.06890.3572-6.255614.363422.6045
30.13270.54370.04910.52960.05110.01830.42530.3351-0.34250.2041-0.3752-0.242-0.0294-0.3028-0.17470.0052-0.652-0.3641-0.7046-0.8345-0.2803-2.32228.41847.8797
40.1173-0.03360.0240.01830.00340.0394-0.0465-0.06220.18660.0336-0.0740.1845-0.0924-0.1564-0.05090.46950.0612-0.06680.41310.26920.4014-14.788122.6427-31.2788
5-0.0016-0.00820.0026-0.00220.0032-0.0034-0.2168-0.0142-0.00590.01810.0204-0.0076-0.0382-0.017-0.00041.31030.08340.04050.2869-0.1630.9161-16.246618.6361-43.7728
6-0.00140.005-0.00580.32360.15350.0676-0.0925-0.0857-0.1030.047-0.14190.1436-0.0636-0.255-0.27480.49870.70020.2981-0.16390.26960.5161-38.403949.9135-2.7002
70.02940.0382-0.00190.03110.00310.00420.36810.124-0.1169-0.19310.01520.07880.091-0.0401-0.00030.8595-0.08840.23270.5165-0.39790.6962-28.543843.5258-9.0068
80.0426-0.06210.00450.1355-0.02060.0074-0.0684-0.0879-0.0239-0.1746-0.0656-0.0950.18290.02950.01890.3349-0.14410.49380.8444-0.49390.3267-31.103935.5542-0.2504
90.1273-0.06040.110.084-0.03970.10120.31430.41990.2548-0.23880.07970.51530.19240.5391-0.0689-0.97680.5046-0.2660.77410.18340.2365-33.404445.9779-1.1199
100.24790.1447-0.0730.1941-0.02750.3728-0.20920.1589-0.1497-0.1328-0.1146-0.07740.3781-0.23690.1020.2918-0.00390.46650.40740.32470.303-30.8966.737725.1458
110.0422-0.0351-0.0230.05040.00860.08550.153-0.0621-0.1924-0.07040.13140.14350.02440.05330.10610.48940.49850.10710.33920.04630.8881-33.004164.022717.6237
120.01970.0426-0.04450.2009-0.13770.1102-0.1930.13610.08760.0031-0.2517-0.0309-0.16150.233-0.11470.89560.63290.040.36030.02170.3075-30.03175.212824.0844
130.1163-0.04610.08060.0020.02230.1220.11130.1380.01040.0425-0.01260.052-0.0641-0.13320.266-0.22890.7529-0.46170.4995-0.70370.8578-39.621972.851523.9145
140.1511-0.0233-0.11640.05260.10010.39140.2305-0.24020.05250.2520.1956-0.3183-0.3777-0.00340.69380.7956-0.2051-0.2641-0.2082-1.0659-1.2126-11.708139.52884.7212
150.12780.02180.02810.26790.03810.0055-0.0773-0.08990.152-0.0228-0.0001-0.16630.29830.35120.0480.76240.03870.15940.20290.01110.3045-6.448740.3817.4455
160.0475-0.0850.04150.2654-0.13760.2160.0908-0.13390.2145-0.17020.0230.07730.17580.02510.08460.12840.18650.4206-0.3209-0.12850.8375-16.776538.56382.9671
170.10820.00070.08960.0674-0.00550.13120.3682-0.1746-0.2120.28580.0180.2625-0.18640.12580.27-0.0169-0.5716-0.507-0.0057-0.7416-0.0036-16.598645.614811.2961
180.00790.0002-0.02850.30250.02990.10950.0469-0.0172-0.0109-0.0081-0.0662-0.0639-0.1631-0.0819-0.06570.2581-0.07660.14330.1335-0.29660.9002-34.878165.987934.8247
190.0719-0.1149-0.01170.23230.09520.16670.15530.1055-0.0095-0.01640.3181-0.10870.01390.03940.45330.16620.05230.15080.7575-0.39210.1578-25.960656.801530.2905
200.17270.15040.02120.1472-0.00360.14180.1194-0.0556-0.11960.1458-0.02450.00770.127-0.11550.03110.404-0.23530.23380.01530.16530.0739-30.277953.436629.1816
210.010.0180.02520.18610.11870.0575-0.3063-0.2750.04230.39360.1590.1937-0.1791-0.0593-0.1390.33790.36440.04730.6020.12480.0843-31.772758.8333.441
220.0120.0207-0.02210.03080.03420.18870.1107-0.0519-0.05020.1824-0.13670.00610.17510.16320.06640.0272-0.2446-0.33910.2041-0.604-0.6088-22.657354.778637.6962
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(CHAIN A AND RESID 1:85 )
2X-RAY DIFFRACTION2(CHAIN A AND RESID 86:145 )
3X-RAY DIFFRACTION3(CHAIN A AND RESID 146:214 )
4X-RAY DIFFRACTION4(CHAIN A AND RESID 215:242 )
5X-RAY DIFFRACTION5(CHAIN A AND RESID 243:255 )
6X-RAY DIFFRACTION6(CHAIN L AND RESID 3:18 )
7X-RAY DIFFRACTION7(CHAIN L AND RESID 19:38 )
8X-RAY DIFFRACTION8(CHAIN L AND RESID 39:58 )
9X-RAY DIFFRACTION9(CHAIN L AND RESID 59:121 )
10X-RAY DIFFRACTION10(CHAIN L AND RESID 122:153 )
11X-RAY DIFFRACTION11(CHAIN L AND RESID 154:180 )
12X-RAY DIFFRACTION12(CHAIN L AND RESID 181:202 )
13X-RAY DIFFRACTION13(CHAIN L AND RESID 203:215 )
14X-RAY DIFFRACTION14(CHAIN H AND RESID 1:69 )
15X-RAY DIFFRACTION15(CHAIN H AND RESID 70:85 )
16X-RAY DIFFRACTION16(CHAIN H AND RESID 86:99 )
17X-RAY DIFFRACTION17(CHAIN H AND RESID 100:120 )
18X-RAY DIFFRACTION18(CHAIN H AND RESID 121:132 )
19X-RAY DIFFRACTION19(CHAIN H AND RESID 133:154 )
20X-RAY DIFFRACTION20(CHAIN H AND RESID 155:171 )
21X-RAY DIFFRACTION21(CHAIN H AND RESID 172:193 )
22X-RAY DIFFRACTION22(CHAIN H AND RESID 194:213 )

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