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- PDB-6pxg: Crystal Structure of MERS-CoV neutralizing antibody G2 Fab -

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Basic information

Entry
Database: PDB / ID: 6pxg
TitleCrystal Structure of MERS-CoV neutralizing antibody G2 Fab
Components
  • G2 Fab Heavy Chain
  • G2 Fab Light chain
KeywordsIMMUNE SYSTEM / antibody / fusion glycoprotein
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsWang, N. / McLellan, J.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R01AI127521 United States
CitationJournal: Cell Rep / Year: 2019
Title: Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD.
Authors: Nianshuang Wang / Osnat Rosen / Lingshu Wang / Hannah L Turner / Laura J Stevens / Kizzmekia S Corbett / Charles A Bowman / Jesper Pallesen / Wei Shi / Yi Zhang / Kwanyee Leung / Robert N ...Authors: Nianshuang Wang / Osnat Rosen / Lingshu Wang / Hannah L Turner / Laura J Stevens / Kizzmekia S Corbett / Charles A Bowman / Jesper Pallesen / Wei Shi / Yi Zhang / Kwanyee Leung / Robert N Kirchdoerfer / Michelle M Becker / Mark R Denison / James D Chappell / Andrew B Ward / Barney S Graham / Jason S McLellan /
Abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into the human population in 2012 and has caused substantial morbidity and mortality. Potently neutralizing antibodies targeting the ...Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into the human population in 2012 and has caused substantial morbidity and mortality. Potently neutralizing antibodies targeting the receptor-binding domain (RBD) on MERS-CoV spike (S) protein have been characterized, but much less is known about antibodies targeting non-RBD epitopes. Here, we report the structural and functional characterization of G2, a neutralizing antibody targeting the MERS-CoV S1 N-terminal domain (S1-NTD). Structures of G2 alone and in complex with the MERS-CoV S1-NTD define a site of vulnerability comprising two loops, each of which contain a residue mutated in G2-escape variants. Cell-surface binding studies and in vitro competition experiments demonstrate that G2 strongly disrupts the attachment of MERS-CoV S to its receptor, dipeptidyl peptidase-4 (DPP4), with the inhibition requiring the native trimeric S conformation. These results advance our understanding of antibody-mediated neutralization of coronaviruses and should facilitate the development of immunotherapeutics and vaccines against MERS-CoV.
History
DepositionJul 26, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: G2 Fab Heavy Chain
B: G2 Fab Light chain
C: G2 Fab Heavy Chain
D: G2 Fab Light chain
E: G2 Fab Heavy Chain
F: G2 Fab Light chain
H: G2 Fab Heavy Chain
L: G2 Fab Light chain


Theoretical massNumber of molelcules
Total (without water)192,5458
Polymers192,5458
Non-polymers00
Water8,827490
1
A: G2 Fab Heavy Chain
B: G2 Fab Light chain


Theoretical massNumber of molelcules
Total (without water)48,1362
Polymers48,1362
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3200 Å2
ΔGint-26 kcal/mol
Surface area19040 Å2
MethodPISA
2
C: G2 Fab Heavy Chain
D: G2 Fab Light chain


Theoretical massNumber of molelcules
Total (without water)48,1362
Polymers48,1362
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3250 Å2
ΔGint-25 kcal/mol
Surface area19350 Å2
MethodPISA
3
E: G2 Fab Heavy Chain
F: G2 Fab Light chain


Theoretical massNumber of molelcules
Total (without water)48,1362
Polymers48,1362
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3260 Å2
ΔGint-25 kcal/mol
Surface area18720 Å2
MethodPISA
4
H: G2 Fab Heavy Chain
L: G2 Fab Light chain


Theoretical massNumber of molelcules
Total (without water)48,1362
Polymers48,1362
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3180 Å2
ΔGint-26 kcal/mol
Surface area19010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.640, 207.140, 103.360
Angle α, β, γ (deg.)90.000, 97.700, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Antibody
G2 Fab Heavy Chain


Mass: 24275.059 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#2: Antibody
G2 Fab Light chain


Mass: 23861.293 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 490 / 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: 2.24 Å3/Da / Density % sol: 45.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 15% EtOH, 40% Pentaerythritol propoxylate (5/4 PO/OH)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.1→39.53 Å / Num. obs: 95880 / % possible obs: 97.6 % / Redundancy: 3.5 % / CC1/2: 0.995 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.059 / Rrim(I) all: 0.113 / Net I/σ(I): 6.2 / Num. measured all: 336364 / Scaling rejects: 238
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.1-2.143.30.8161524346080.6810.50.9591.693.9
11.5-39.533.40.06218415440.9920.0390.07311.187.6

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
Aimless0.2.8data scaling
PDB_EXTRACT3.24data extraction
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→38.406 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2248 4756 4.98 %
Rwork0.1812 90796 -
obs0.1834 95552 97.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 139.09 Å2 / Biso mean: 56.1338 Å2 / Biso min: 19.16 Å2
Refinement stepCycle: final / Resolution: 2.1→38.406 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12925 0 0 490 13415
Biso mean---50.76 -
Num. residues----1705
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 (%)
2.1-2.12390.34011370.30282956309393
2.1239-2.14890.30251420.28152938308093
2.1489-2.17510.31381400.27572860300095
2.1751-2.20260.31611350.26772988312395
2.2026-2.23160.30461470.26162958310595
2.2316-2.26210.29331540.26472981313595
2.2621-2.29440.30461320.25012951308395
2.2944-2.32870.31121490.2422959310896
2.3287-2.36510.31361510.24133027317896
2.3651-2.40380.30031610.2343036319796
2.4038-2.44530.26151670.22712929309697
2.4453-2.48970.31941490.22373020316997
2.4897-2.53760.28931610.22943118327997
2.5376-2.58940.28471750.22542941311697
2.5894-2.64570.26751820.21283007318998
2.6457-2.70720.26531670.21733114328198
2.7072-2.77490.24691540.21192999315399
2.7749-2.84990.24911660.21733077324399
2.8499-2.93380.26311630.21093090325399
2.9338-3.02840.27561620.19643041320399
3.0284-3.13660.21261810.19123131331299
3.1366-3.26210.23771610.18493009317099
3.2621-3.41050.25161940.18263112330699
3.4105-3.59020.18091360.1663068320499
3.5902-3.81490.20911650.1543085325099
3.8149-4.10920.17421790.14733105328499
4.1092-4.52210.16341470.12393118326599
4.5221-5.17510.15261550.12593092324799
5.1751-6.51490.20721700.15033091326199
6.5149-38.4120.18671740.15782995316995
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)
14.62222.5080.74932.7943-0.17944.3088-0.4682-0.8069-0.1527-0.3345-0.0331-0.14370.33170.19380.43120.60020.30220.04850.51360.04160.269842.88.62210.576
21.7015-0.54631.49883.2867-1.32965.59380.1667-0.027-0.11980.03650.02570.1152-0.061-0.2009-0.16420.1178-0.03970.0580.25910.03070.249524.729-7.993187.561
34.10920.1908-1.23322.18052.26495.9704-0.3725-0.06391.1220.48590.5724-0.1588-0.3069-0.3261-0.35220.77120.1707-0.24730.30640.05960.665333.60226.911192.701
45.5950.1521-1.60342.9709-1.27666.0056-0.285-0.1950.94260.17820.1355-0.1233-0.55670.51790.08820.58750.0453-0.20290.2637-0.0050.483442.46423.896196.817
56.433.07046.81682.1853.49897.3245-0.48160.38780.65810.4160.13720.0127-0.52540.08390.35190.38230.0099-0.02450.3130.10120.314327.86317.26179.837
63.92472.8052-0.37953.857-1.53441.67460.042-0.05140.04870.1789-0.0050.3458-0.2437-0.41460.01570.19480.06020.10090.45030.02440.30112.1212.336183.196
72.8117-4.6183-2.91688.88845.78299.06220.13310.9563-0.1588-1.8963-0.5950.6441-1.188-0.30470.30350.7255-0.1807-0.10220.4986-0.08340.542110.392-39.423173.567
84.60630.23951.64937.10844.12496.4674-0.00790.30370.1628-0.6882-0.41330.5961-0.5776-0.61070.42970.541-0.0492-0.15980.3578-0.02440.39373.969-48.515170.905
92.75581.86172.37724.34692.6424.3193-0.0599-0.01620.0023-0.2796-0.16390.2868-0.0546-0.15730.21260.1917-0.02280.03190.22820.05570.219714.32-38.501185.917
106.44311.33343.77564.8457-0.14365.70480.09540.0229-0.2564-0.0111-0.1214-0.28810.22460.42290.04860.2040.01280.05140.21220.01340.227827.833-29.024195.023
111.3864-0.5495-0.08873.8740.90383.29660.4487-0.1493-0.84770.9283-0.1102-0.57471.69270.2533-0.15481.3807-0.1008-0.32890.32360.00140.684215.363-64.171184.312
121.6012-0.21630.27680.06030.25172.96220.3176-0.0086-0.27380.2003-0.0867-0.2230.64540.0527-0.2530.4314-0.0036-0.04440.19880.09520.308820.235-44.068199.651
132.5866-1.00980.21726.76350.09395.42780.3078-0.2807-0.20770.2197-0.15380.18620.056-0.343-0.14450.2678-0.0846-0.01810.34620.07270.32319.756-37.335210.47
142.3756-1.48751.72435.33650.83474.1985-0.23560.34231.22780.059-0.6179-1.2961-0.73460.41510.57560.603-0.0016-0.23340.44760.20910.893916.068-44.336121.885
156.4897-1.12253.03816.2999-0.39696.7734-0.14370.28660.86810.2438-0.3349-0.4922-0.1974-0.48320.43150.3743-0.0201-0.15760.31420.08630.519510.843-47.877121.281
161.39041.99350.12842.85260.25763.32910.184-0.208-0.1978-1.244-0.82580.36830.05370.50890.24650.86740.2189-0.20430.5212-0.02730.487729.257-30.566143.577
173.34860.97712.63527.3188-1.84767.76250.2011-0.17710.1439-1.0269-0.9108-0.15820.01420.73460.61110.6390.1582-0.03370.64770.12060.378433.246-28.203146.664
186.5887-4.26711.85295.3831-1.1426.02480.0728-0.3637-0.48240.74320.0881-0.10610.6312-0.2181-0.10330.7736-0.0765-0.21720.29420.05350.525120.959-63.867133.742
191.13590.86082.28881.08031.23355.1760.41760.0379-0.14350.3974-0.22190.00940.7661-0.0619-0.20620.28490.00320.02990.41-0.02470.311324.197-45.173147.046
203.7576-1.85470.69488.3663-0.53852.92870.3780.1738-0.24880.0717-0.44350.41480.15560.00820.04570.3351-0.0621-0.0810.3741-0.01220.332726.193-38.018160.143
217.61075.4987-1.52564.3553-0.75952.513-0.545-0.7499-0.8013-0.5718-0.2341-0.61020.62890.54260.74080.57610.27740.14750.49220.14370.405949.2190.825157.801
222.4132.48351.31524.4985-0.17035.3447-0.3069-0.68480.3359-0.3221-0.31820.0996-0.398-0.20680.57570.46760.1915-0.00030.4093-0.00870.227650.20513.837160.596
232.10931.15592.00751.06921.31723.8569-0.0675-0.35440.0422-0.0994-0.1490.035-0.3273-0.34890.21420.38540.21420.05060.36950.07120.306141.8992.23151.881
242.50160.01941.86386.8018-3.19728.10460.3270.0407-0.2242-0.1856-0.39070.01110.18950.46160.07470.22660.08190.00870.47580.03340.303332.204-9.145134.823
254.072-0.7021-2.74642.28972.48693.73420.07840.34770.781-0.09680.2091-0.0596-0.9354-0.6087-0.37520.91580.0959-0.18010.33330.07430.489739.99125.295139.775
265.870.53960.10952.7405-2.72965.7393-0.48270.06810.6027-0.36870.1097-0.1616-0.64590.47890.33850.9670.0734-0.13120.34320.06080.387749.18824.398143.289
271.7364-0.07611.01720.77470.19461.7503-0.0947-0.0141-0.03270.24090.05540.3149-0.4344-0.33850.0680.40520.16430.0370.48530.01840.311426.0797.088135.518
284.72712.81640.01785.3628-2.56022.98060.163-0.2058-0.33080.31560.12540.5462-0.3324-0.5286-0.26540.33970.17020.07310.65350.0190.385418.8332.607132.076
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 2:106 )A2 - 106
2X-RAY DIFFRACTION2( CHAIN A AND RESID 107:213 )A107 - 213
3X-RAY DIFFRACTION3( CHAIN B AND RESID 1:25 )B1 - 25
4X-RAY DIFFRACTION4( CHAIN B AND RESID 26:101 )B26 - 101
5X-RAY DIFFRACTION5( CHAIN B AND RESID 102:113 )B102 - 113
6X-RAY DIFFRACTION6( CHAIN B AND RESID 114:212 )B114 - 212
7X-RAY DIFFRACTION7( CHAIN C AND RESID 1:17 )C1 - 17
8X-RAY DIFFRACTION8( CHAIN C AND RESID 18:82 )C18 - 82
9X-RAY DIFFRACTION9( CHAIN C AND RESID 83:145 )C83 - 145
10X-RAY DIFFRACTION10( CHAIN C AND RESID 146:213 )C146 - 213
11X-RAY DIFFRACTION11( CHAIN D AND RESID 1:90 )D1 - 90
12X-RAY DIFFRACTION12( CHAIN D AND RESID 91:143 )D91 - 143
13X-RAY DIFFRACTION13( CHAIN D AND RESID 144:212 )D144 - 212
14X-RAY DIFFRACTION14( CHAIN E AND RESID 2:44 )E2 - 44
15X-RAY DIFFRACTION15( CHAIN E AND RESID 45:106 )E45 - 106
16X-RAY DIFFRACTION16( CHAIN E AND RESID 107:165 )E107 - 165
17X-RAY DIFFRACTION17( CHAIN E AND RESID 166:213 )E166 - 213
18X-RAY DIFFRACTION18( CHAIN F AND RESID 1:90 )F1 - 90
19X-RAY DIFFRACTION19( CHAIN F AND RESID 91:128 )F91 - 128
20X-RAY DIFFRACTION20( CHAIN F AND RESID 129:212 )F129 - 212
21X-RAY DIFFRACTION21( CHAIN H AND RESID 2:25 )H2 - 25
22X-RAY DIFFRACTION22( CHAIN H AND RESID 26:66 )H26 - 66
23X-RAY DIFFRACTION23( CHAIN H AND RESID 67:145 )H67 - 145
24X-RAY DIFFRACTION24( CHAIN H AND RESID 146:213 )H146 - 213
25X-RAY DIFFRACTION25( CHAIN L AND RESID 1:18 )L1 - 18
26X-RAY DIFFRACTION26( CHAIN L AND RESID 19:90 )L19 - 90
27X-RAY DIFFRACTION27( CHAIN L AND RESID 91:155 )L91 - 155
28X-RAY DIFFRACTION28( CHAIN L AND RESID 156:212 )L156 - 212

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