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- PDB-7k8p: Crystal structure of an anti-SARS-CoV-2 human neutralizing antibo... -

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Basic information

Entry
Database: PDB / ID: 7k8p
TitleCrystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C110
Components
  • C110 Fab Heavy Chain
  • C110 Fab Light Chain
KeywordsIMMUNE SYSTEM / Human Neutralizing Antibody / SARS-CoV-2 / Receptor Binding Domain / COVID-19
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDam, K.A. / Barnes, C.O. / Bjorkman, P.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01-AI138938-S1 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P50 AI150464-13 United States
CitationJournal: Nature / Year: 2020
Title: SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.
Authors: Christopher O Barnes / Claudia A Jette / Morgan E Abernathy / Kim-Marie A Dam / Shannon R Esswein / Harry B Gristick / Andrey G Malyutin / Naima G Sharaf / Kathryn E Huey-Tubman / Yu E Lee / ...Authors: Christopher O Barnes / Claudia A Jette / Morgan E Abernathy / Kim-Marie A Dam / Shannon R Esswein / Harry B Gristick / Andrey G Malyutin / Naima G Sharaf / Kathryn E Huey-Tubman / Yu E Lee / Davide F Robbiani / Michel C Nussenzweig / Anthony P West / Pamela J Bjorkman /
Abstract: The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute ...The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein show promise therapeutically and are being evaluated clinically. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.
History
DepositionSep 27, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: C110 Fab Heavy Chain
L: C110 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)49,5192
Polymers49,5192
Non-polymers00
Water3,063170
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3170 Å2
ΔGint-23 kcal/mol
Surface area18820 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)48.498, 62.738, 78.423
Angle α, β, γ (deg.)90.000, 97.508, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Antibody C110 Fab Heavy Chain


Mass: 25866.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#2: Antibody C110 Fab Light Chain


Mass: 23653.180 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 170 / 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: 48.51 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.3
Details: 0.2 M sodium tartrate dibasic dihydrate, 20 % w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-1 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 19, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.8→38.9 Å / Num. obs: 42891 / % possible obs: 98.8 % / Redundancy: 4.7 % / Biso Wilson estimate: 23.83 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.087 / Rpim(I) all: 0.041 / Net I/σ(I): 7.7
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 2 % / Rmerge(I) obs: 1.07 / Mean I/σ(I) obs: 2 / Num. unique obs: 4284 / CC1/2: 0.78 / Rpim(I) all: 0.82 / % possible all: 78.2

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
Blu-Icedata collection
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6XCA
Resolution: 1.8→38.69 Å / SU ML: 0.2005 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.6076
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2292 2181 5.09 %
Rwork0.1964 40681 -
obs0.1981 42862 98.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.97 Å2
Refinement stepCycle: LAST / Resolution: 1.8→38.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3171 0 0 170 3341
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01043255
X-RAY DIFFRACTIONf_angle_d1.20954448
X-RAY DIFFRACTIONf_chiral_restr0.0936504
X-RAY DIFFRACTIONf_plane_restr0.0081568
X-RAY DIFFRACTIONf_dihedral_angle_d13.5286455
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.840.30681470.27792513X-RAY DIFFRACTION98.92
1.84-1.880.32671390.25172540X-RAY DIFFRACTION99.52
1.88-1.930.26861340.22332543X-RAY DIFFRACTION99.33
1.93-1.980.26181260.21462553X-RAY DIFFRACTION99.15
1.98-2.040.24611320.21072507X-RAY DIFFRACTION98.65
2.04-2.110.21261340.19342529X-RAY DIFFRACTION98.08
2.11-2.180.2381290.19882500X-RAY DIFFRACTION97.51
2.18-2.270.23341410.19722546X-RAY DIFFRACTION99.52
2.27-2.370.26491360.21972533X-RAY DIFFRACTION99.22
2.37-2.50.25011250.21372562X-RAY DIFFRACTION99.3
2.5-2.650.24481460.21582552X-RAY DIFFRACTION99.41
2.65-2.860.22841430.21962559X-RAY DIFFRACTION99.12
2.86-3.140.26911330.21052483X-RAY DIFFRACTION96.42
3.14-3.60.25281470.19842575X-RAY DIFFRACTION99.93
3.6-4.530.1771270.16362591X-RAY DIFFRACTION99.56
4.53-38.690.18571420.16762595X-RAY DIFFRACTION97.65
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)
12.90804283957-2.357678462431.547769959954.62778488573-2.872375343552.69373189490.2633521891050.184146025096-0.395605703027-0.502693800926-0.2496323441720.6385440686170.17269632830.0868770120935-0.01511298324450.188493162870.00328912749329-0.02288925700960.133307548407-0.02377176369090.233865003754-21.8263198438-26.6527335682-6.39725894142
22.66165482101-0.272336433722-0.4390583668240.8171692903310.7406716483151.106134865610.176413532306-0.0666628291448-0.105062759942-0.0890894473526-0.1378161204150.0436430834080.07395492037690.0296674605217-0.02639292689330.171391818369-0.00690083769943-0.02062154163770.1241538761370.005256023009140.185659822573-16.3633715169-31.29944875162.80823933774
31.79823063062-0.3959641785350.008364113480351.97609399061-1.225321010821.702555593880.0615365874781-0.0750567330350.2028196556680.231153719251-0.061196611785-0.0149603992439-0.2118103592180.0486022310109-0.008736379368970.21782648967-0.006605494284750.008622021448990.119530885524-0.04205170798860.21937978736-17.7170585526-23.12811628653.22811558623
43.23750019374-0.5858543739650.2388232456194.39005846386-0.5718624690131.177618234520.082776787455-0.48360668864-0.3471018481430.514862392395-0.0755879310079-0.2728364882760.1527845703540.0992815618566-0.08899798053060.222746935013-0.018395066261-0.01363819636980.2136128894730.01307872380360.264752552228-11.8884826416-32.0555092263.55986461728
53.72527973416-0.490498695209-1.886524580030.823982404995-0.1780153014241.78217669417-0.1973427583461.02276394806-0.381184716868-0.0605568830086-0.06484037142130.03693989301140.17312170721-0.3847709923840.2102024160540.247864472961-0.03262890603450.005932668985550.455479073312-0.09307534237580.231235915561-12.7352679269-21.0849485695-32.41913701
61.97298640976-0.851889153869-1.504953932551.939979977471.884372930434.995696325620.047047083012-0.14020970470.2019791765080.110245560042-0.0238102775854-0.3033249159740.005196341323590.4998216099270.00496031693120.237752848009-0.0287675953172-0.01380750234290.3376688372860.05989247489710.38308633111510.1358444817-26.0143677283-6.20294621434
74.7826933101-0.202777779588-0.0501155945463.081703755540.5658263060094.95501510644-0.0208613686123-0.234392584051-0.007517736300460.195516590368-0.0962668751131-0.1498679902680.1039068996110.2360721384940.1028277333140.1357885025580.00156893927305-0.01782427854040.1601409738160.03912142974470.2218902728813.22613663966-31.6894226551.62442370017
83.80639653096-0.8814131089690.4036781413633.518586879030.8259923720034.45743371752-0.135208149992-0.2979275704850.4841991667240.3943321051910.0871011672584-0.3807326263660.1838153701810.6742400346650.03051557431660.161618582068-0.0109731459025-0.02600930985490.3193004411990.03753454153860.32729268892410.8292892137-30.68077048373.34606119666
93.25002055694-1.2203717675-2.2520622112.632890440940.5722135922864.77995577033-0.02295810254940.0778912807464-0.2457130477870.0226885986952-0.167004228961-0.2685302697930.3719243063780.4303250890350.1745726775410.1764277746180.0187595484309-0.007049537409050.2372706241940.01625274472380.2917560286494.59503529781-31.8686407046-6.75987673385
101.259920653930.229716071847-1.710629679360.664198996792-0.5137220502775.057689084650.0108617709201-0.06301946229080.02235373434140.0398800607185-0.0668779304420.0008122166227280.0004979950688670.2345292337660.02981825301840.208245766526-0.00712240495208-0.03619991328640.2195503602750.01838339371420.2561397993283.8830414837-24.3063650515-6.47290522314
114.69593580729-0.407640859194-0.7884332239773.72395206717-0.2982759565731.54460969438-0.0244448921690.4612954612150.7216350772090.01492078642240.1642562893870.242537582255-0.405055574537-0.158868286822-0.07858711257190.2733065131860.00731907904730.001744287777330.3206937457140.08489550235420.308949612345-1.73305097367-9.91100028952-30.5894069445
124.37693927868-1.434040902060.6370860589683.63606225443-2.03586497592.94473408852-0.02758146279270.4282351318380.753274734317-0.02324160250540.0425692939459-0.0767857274834-0.3295314159860.0007970881720560.09634897353380.283576255827-0.0046157748291-0.01336576590060.2936706095710.07672968861990.3348938841511.35519240392-10.8147488587-31.5012737135
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'H' and (resid 1 through 17 )HA1 - 171 - 17
22chain 'H' and (resid 18 through 40 )HA18 - 4018 - 40
33chain 'H' and (resid 41 through 91 )HA41 - 9141 - 95
44chain 'H' and (resid 92 through 114 )HA92 - 11496 - 129
55chain 'H' and (resid 115 through 212 )HA115 - 212130 - 216
66chain 'L' and (resid 2 through 18 )LB2 - 181 - 17
77chain 'L' and (resid 19 through 61 )LB19 - 6118 - 60
88chain 'L' and (resid 62 through 75 )LB62 - 7561 - 74
99chain 'L' and (resid 76 through 90 )LB76 - 9075 - 89
1010chain 'L' and (resid 91 through 113 )LB91 - 11390 - 112
1111chain 'L' and (resid 114 through 163 )LB114 - 163113 - 162
1212chain 'L' and (resid 164 through 211 )LB164 - 211163 - 212

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