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- PDB-5vzr: Crystal Structure of MERS-CoV neutralizing antibody G4 Fab -

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Basic information

Entry
Database: PDB / ID: 5vzr
TitleCrystal Structure of MERS-CoV neutralizing antibody G4 Fab
Components
  • G4 antibody heavy chain
  • G4 antibody light chain
KeywordsIMMUNE SYSTEM / antibody / neutralizing
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.57 Å
AuthorsWang, N. / Wrapp, D. / McLellan, J.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI127521 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2017
Title: Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen.
Authors: Jesper Pallesen / Nianshuang Wang / Kizzmekia S Corbett / Daniel Wrapp / Robert N Kirchdoerfer / Hannah L Turner / Christopher A Cottrell / Michelle M Becker / Lingshu Wang / Wei Shi / Wing- ...Authors: Jesper Pallesen / Nianshuang Wang / Kizzmekia S Corbett / Daniel Wrapp / Robert N Kirchdoerfer / Hannah L Turner / Christopher A Cottrell / Michelle M Becker / Lingshu Wang / Wei Shi / Wing-Pui Kong / Erica L Andres / Arminja N Kettenbach / Mark R Denison / James D Chappell / Barney S Graham / Andrew B Ward / Jason S McLellan /
Abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus that since its emergence in 2012 has caused outbreaks in human populations with case-fatality rates of ∼36%. ...Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus that since its emergence in 2012 has caused outbreaks in human populations with case-fatality rates of ∼36%. As in other coronaviruses, the spike (S) glycoprotein of MERS-CoV mediates receptor recognition and membrane fusion and is the primary target of the humoral immune response during infection. Here we use structure-based design to develop a generalizable strategy for retaining coronavirus S proteins in the antigenically optimal prefusion conformation and demonstrate that our engineered immunogen is able to elicit high neutralizing antibody titers against MERS-CoV. We also determined high-resolution structures of the trimeric MERS-CoV S ectodomain in complex with G4, a stem-directed neutralizing antibody. The structures reveal that G4 recognizes a glycosylated loop that is variable among coronaviruses and they define four conformational states of the trimer wherein each receptor-binding domain is either tightly packed at the membrane-distal apex or rotated into a receptor-accessible conformation. Our studies suggest a potential mechanism for fusion initiation through sequential receptor-binding events and provide a foundation for the structure-based design of coronavirus vaccines.
History
DepositionMay 29, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 30, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Sep 27, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 2.0Dec 11, 2019Group: Author supporting evidence / Polymer sequence / Category: entity_poly / pdbx_audit_support
Item: _entity_poly.pdbx_seq_one_letter_code_can / _pdbx_audit_support.funding_organization
Revision 2.1Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: G4 antibody heavy chain
L: G4 antibody light chain
A: G4 antibody heavy chain
B: G4 antibody light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,4175
Polymers98,3254
Non-polymers921
Water17,168953
1
H: G4 antibody heavy chain
L: G4 antibody light chain


Theoretical massNumber of molelcules
Total (without water)49,1632
Polymers49,1632
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3630 Å2
ΔGint-27 kcal/mol
Surface area19750 Å2
MethodPISA
2
A: G4 antibody heavy chain
B: G4 antibody light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,2553
Polymers49,1632
Non-polymers921
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3750 Å2
ΔGint-27 kcal/mol
Surface area19650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.678, 88.759, 128.469
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 G4 antibody heavy chain


Mass: 25295.322 Da / Num. of mol.: 2 / Fragment: Fab fragment
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#2: Antibody G4 antibody light chain


Mass: 23867.367 Da / Num. of mol.: 2 / Fragment: Fab fragment
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 953 / Source method: isolated from a natural source / Formula: H2O

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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: 2.39 Å3/Da / Density % sol: 48.46 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M MES pH 6.5, 0.2 M magnesium chloride and 10% (w/w) PEG4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97926 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Feb 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97926 Å / Relative weight: 1
ReflectionResolution: 1.57→88.76 Å / Num. obs: 128851 / % possible obs: 99.8 % / Redundancy: 6.1 % / Biso Wilson estimate: 17.7 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.128 / Net I/σ(I): 7.8 / Num. measured all: 786682 / Scaling rejects: 1746
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Net I/σ(I) obs% possible all
1.57-1.66.31.6414001163390.6011.799.8
8.6-88.766.20.06456609150.95119.3100

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
Aimless0.5.21data scaling
PDB_EXTRACT3.22data extraction
iMOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDBIDs 2JEL and 3QQ9
Resolution: 1.57→73.025 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 23.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2151 6415 4.99 %
Rwork0.1823 122183 -
obs0.1839 128598 99.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 85.14 Å2 / Biso mean: 27.4222 Å2 / Biso min: 9.29 Å2
Refinement stepCycle: final / Resolution: 1.57→73.025 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6560 0 6 953 7519
Biso mean--35.02 38.34 -
Num. residues----852
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0066748
X-RAY DIFFRACTIONf_angle_d0.8499193
X-RAY DIFFRACTIONf_chiral_restr0.0561034
X-RAY DIFFRACTIONf_plane_restr0.0051167
X-RAY DIFFRACTIONf_dihedral_angle_d13.4254042
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.57-1.58780.35031990.299940514250100
1.5878-1.60650.33262100.289239904200100
1.6065-1.62610.28832210.28334044426599
1.6261-1.64670.32572200.273140544274100
1.6467-1.66840.30422110.255240054216100
1.6684-1.69120.28622080.246640304238100
1.6912-1.71540.25342270.24534005423299
1.7154-1.7410.26961950.22474060425599
1.741-1.76820.26562010.23113988418999
1.7682-1.79720.28032240.223740354259100
1.7972-1.82820.26942030.204340504253100
1.8282-1.86140.22142030.196940374240100
1.8614-1.89720.22152090.19740754284100
1.8972-1.9360.22562190.183640344253100
1.936-1.97810.2042250.185140604285100
1.9781-2.02410.22492220.185640334255100
2.0241-2.07470.21532260.177140314257100
2.0747-2.13080.20882040.175940634267100
2.1308-2.19350.20442080.176840824290100
2.1935-2.26430.2192090.178340994308100
2.2643-2.34520.19252000.179840534253100
2.3452-2.43910.23712270.182740784305100
2.4391-2.55020.20632060.188440964302100
2.5502-2.68460.20482190.184340924311100
2.6846-2.85280.23742460.1840514297100
2.8528-3.07310.19262140.172641344348100
3.0731-3.38230.1911930.166441624355100
3.3823-3.87180.20222040.152641634367100
3.8718-4.87790.17632280.139141884416100
4.8779-73.10440.1912340.1814340457499
Refinement TLS params.

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

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
14.5179-0.3755-0.91411.86190.31882.28970.07330.13290.30060.1304-0.0598-0.0007-0.1206-0.2593-0.0030.12270.01570.00830.1175-0.01290.142435.804857.798637.8992
21.6970.1937-0.36832.4110.24292.2917-0.1330.0508-0.15580.06490.0382-0.00040.1404-0.11670.09940.11570.01640.03290.0824-0.02210.142739.884947.210233.2547
33.80760.9981-0.4995.7918-0.05574.498-0.40730.63420.0122-0.47450.1908-0.2617-0.3150.1240.02320.1982-0.0426-0.00240.20180.01330.11640.308150.096123.848
42.3679-0.0981-0.04833.30151.1852.97750.00530.25120.0164-0.4282-0.16160.3-0.0961-0.5240.11560.19840.0373-0.0210.2837-0.02250.131934.24153.2725.3317
53.088-0.3316-0.47792.50590.39182.1436-0.02360.60360.1738-0.0971-0.06150.3498-0.0576-0.74130.12490.1410.0174-0.00530.3106-0.03810.166829.439856.120632.4077
61.5516-0.928-1.03573.77552.27783.8767-0.11180.079-0.1450.12690.1691-0.31990.30860.22770.05430.1470.00350.04540.1194-0.02010.179843.549842.321530.5859
70.7851-0.3314-0.48190.88160.61781.8504-0.02450.0334-0.05210.0591-0.0347-0.04680.111-0.2624-0.01280.1114-0.0053-0.00250.12960.00980.139930.451653.213652.3192
81.6677-0.27620.85862.2148-0.77244.18610.05410.0482-0.19780.00750.086-0.06540.2176-0.0018-0.14960.0930.0234-0.00830.1092-0.01540.124830.52250.460562.2967
91.7489-0.42751.66772.3909-1.79246.41220.0425-0.0074-0.04690.20030.0495-0.0228-0.14460.0458-0.04960.10990.00830.00710.0908-0.00840.103633.10357.73569.0127
101.29310.42710.23932.5131-1.28785.60990.0606-0.0188-0.12860.29350.0760.10240.6214-0.0845-0.0720.3115-0.01290.03830.1052-0.02040.182233.753425.916240.0007
112.8071.6591-2.72432.0213-0.33714.3083-0.30840.3474-0.1775-0.2480.12150.1120.49680.00550.0340.27060.00440.04920.1486-0.02770.166439.675528.115721.6016
122.9940.71330.00985.01020.93275.7060.1503-0.0799-0.00560.3667-0.0315-0.22060.15990.3266-0.17860.186-0.00750.00220.1537-0.00150.131441.949435.125639.5582
130.4367-0.095-0.77141.22370.94882.0313-0.0247-0.0264-0.07120.22870.0831-0.00210.27990.2273-0.08090.2144-0.00520.02410.1294-0.01760.162938.57130.32236.8286
140.0906-0.0528-0.67730.03140.38345.0050.0170.0104-0.11440.19240.0837-0.05360.8479-0.0583-0.05170.4743-0.03120.05290.16430.01710.21533.489827.870957.1752
152.4448-2.057-1.37654.95590.99863.47210.08470.20190.08060.17070.16220.14570.1079-0.68760.02040.11960.00140.05720.21680.05310.176823.301144.908267.8296
163.4699-2.2132-2.01252.25331.11052.8508-0.18450.4106-0.34590.0778-0.00490.41040.5976-1.10640.08760.1385-0.08490.02220.47260.00840.234217.988241.497865.8816
173.4621-2.7189-1.03085.59581.6391.9587-0.3644-0.2925-0.31020.77610.24810.22230.8398-0.53330.11580.4313-0.04940.13510.32920.08290.328218.998136.932975.2518
181.6014-0.8732-0.54071.81790.83631.4982-0.0272-0.0040.0413-0.26250.0836-0.1862-0.07440.1298-0.03340.1409-0.02060.04310.1154-0.00890.160577.457854.482531.7824
191.6305-0.5711.22371.663-0.98154.09620.0163-0.0615-0.12350.08370.0062-0.00950.04360.1312-0.02230.0820.01490.00820.10410.00790.099471.129756.461464.4218
202.5969-1.01522.43362.5403-2.2717.8596-0.098-0.0893-0.13340.43110.07530.1570.76020.1541-0.10680.36310.08790.09240.14840.03250.25274.727429.245740.0962
213.90840.7583-4.14342.26470.95815.8681-0.29280.0729-0.2092-0.05890.19240.240.33420.13950.210.22660.03150.05910.11880.01660.182580.108631.624321.605
222.8179-0.26011.86725.70651.28326.193-0.133-0.2007-0.05370.38050.2096-0.02920.35310.575-0.3150.13720.05760.04160.22620.02260.153182.386539.143639.9121
230.70810.02150.71020.14270.73294.5781-0.105-0.0394-0.21950.2560.3112-0.05980.57540.6388-0.04550.3140.11290.05690.2152-0.00610.238281.129627.739834.8224
240.7776-0.49470.01440.991-0.1143.0333-0.2027-0.1722-0.12110.36380.1857-0.05240.46250.5536-0.06740.32040.13130.02840.23860.01360.181280.768634.728544.3487
251.9955-0.3886-1.81841.56920.83543.21620.0463-0.050.0946-0.1335-0.0230.2278-0.04220.0932-0.07090.17170.01930.02880.12460.02770.192574.503140.154427.1733
260.1585-0.0587-0.76370.01910.26623.6422-0.1129-0.0694-0.09860.17430.1218-0.07220.67420.2393-0.0050.4050.11940.06040.18140.03870.223974.864831.307557.2581
272.7126-2.1107-1.47145.12151.35883.51690.10820.10050.0532-0.0005-0.05240.03290.1183-0.12120.02780.07870.01010.02010.11420.02560.162164.222847.532467.9204
288.7088-2.2052-4.71762.51531.08936.1815-0.2610.3144-0.8434-0.1205-0.06570.65010.505-0.4870.31040.2241-0.04640.02890.2037-0.01470.315852.921141.308369.8412
294.318-2.7002-2.23693.04680.90953.0540.06940.2387-0.1033-0.1088-0.09480.14590.2615-0.2641-0.0160.1285-0.0199-0.00830.1164-0.00390.173360.656945.515565.7668
303.9293-2.3377-0.87154.0459-0.14321.1606-0.3793-0.2905-0.35180.48610.18250.16440.6542-0.02940.07510.25510.01870.07750.1540.06420.243661.099839.016474.9796
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'H' and (resid 2 through 25 )H2 - 25
2X-RAY DIFFRACTION2chain 'H' and (resid 26 through 45 )H26 - 45
3X-RAY DIFFRACTION3chain 'H' and (resid 46 through 56 )H46 - 56
4X-RAY DIFFRACTION4chain 'H' and (resid 57 through 75 )H57 - 75
5X-RAY DIFFRACTION5chain 'H' and (resid 76 through 87 )H76 - 87
6X-RAY DIFFRACTION6chain 'H' and (resid 88 through 100D)H88 - 100
7X-RAY DIFFRACTION7chain 'H' and (resid 100E through 134 )H100
8X-RAY DIFFRACTION8chain 'H' and (resid 135 through 197 )H135 - 197
9X-RAY DIFFRACTION9chain 'H' and (resid 198 through 225 )H198 - 225
10X-RAY DIFFRACTION10chain 'L' and (resid 1 through 25 )L1 - 25
11X-RAY DIFFRACTION11chain 'L' and (resid 26 through 32 )L26 - 32
12X-RAY DIFFRACTION12chain 'L' and (resid 33 through 61 )L33 - 61
13X-RAY DIFFRACTION13chain 'L' and (resid 62 through 101 )L62 - 101
14X-RAY DIFFRACTION14chain 'L' and (resid 102 through 113 )L102 - 113
15X-RAY DIFFRACTION15chain 'L' and (resid 114 through 143 )L114 - 143
16X-RAY DIFFRACTION16chain 'L' and (resid 144 through 198 )L144 - 198
17X-RAY DIFFRACTION17chain 'L' and (resid 199 through 213 )L199 - 213
18X-RAY DIFFRACTION18chain 'A' and (resid 2 through 111 )A2 - 111
19X-RAY DIFFRACTION19chain 'A' and (resid 112 through 223 )A112 - 223
20X-RAY DIFFRACTION20chain 'B' and (resid 1 through 25 )B1 - 25
21X-RAY DIFFRACTION21chain 'B' and (resid 26 through 32 )B26 - 32
22X-RAY DIFFRACTION22chain 'B' and (resid 33 through 61 )B33 - 61
23X-RAY DIFFRACTION23chain 'B' and (resid 62 through 75 )B62 - 75
24X-RAY DIFFRACTION24chain 'B' and (resid 76 through 90 )B76 - 90
25X-RAY DIFFRACTION25chain 'B' and (resid 91 through 101 )B91 - 101
26X-RAY DIFFRACTION26chain 'B' and (resid 102 through 113 )B102 - 113
27X-RAY DIFFRACTION27chain 'B' and (resid 114 through 144 )B114 - 144
28X-RAY DIFFRACTION28chain 'B' and (resid 145 through 155 )B145 - 155
29X-RAY DIFFRACTION29chain 'B' and (resid 156 through 197 )B156 - 197
30X-RAY DIFFRACTION30chain 'B' and (resid 198 through 213 )B198 - 213

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