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- PDB-7s8g: Structure of anti-LASV Fab 25.10C with FNQI mutation -

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Basic information

Entry
Database: PDB / ID: 7s8g
TitleStructure of anti-LASV Fab 25.10C with FNQI mutation
Components
  • 25.10C-FNQI Fab Heavy Chain
  • 25.10C-FNQI Fab Light Chain
KeywordsANTIVIRAL PROTEIN / IMMUNE SYSTEM / anti-LASV Fab / elbow mutation / domain swap
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.57 Å
AuthorsHastie, K.M. / Enriquez, A.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19A142790 United States
CitationJournal: Cell Rep / Year: 2022
Title: Delineating the mechanism of anti-Lassa virus GPC-A neutralizing antibodies.
Authors: Adrian S Enriquez / Tierra K Buck / Haoyang Li / Michael J Norris / Alex Moon-Walker / Michelle A Zandonatti / Stephanie S Harkins / James E Robinson / Luis M Branco / Robert F Garry / Erica ...Authors: Adrian S Enriquez / Tierra K Buck / Haoyang Li / Michael J Norris / Alex Moon-Walker / Michelle A Zandonatti / Stephanie S Harkins / James E Robinson / Luis M Branco / Robert F Garry / Erica Ollmann Saphire / Kathryn M Hastie /
Abstract: Lassa virus (LASV) is the etiologic agent of Lassa Fever, a hemorrhagic disease that is endemic to West Africa. During LASV infection, LASV glycoprotein (GP) engages with multiple host receptors for ...Lassa virus (LASV) is the etiologic agent of Lassa Fever, a hemorrhagic disease that is endemic to West Africa. During LASV infection, LASV glycoprotein (GP) engages with multiple host receptors for cell entry. Neutralizing antibodies against GP are rare and principally target quaternary epitopes displayed only on the metastable, pre-fusion conformation of GP. Currently, the structural features of the neutralizing GPC-A antibody competition group are understudied. Structures of two GPC-A antibodies presented here demonstrate that they bind the side of the pre-fusion GP trimer, bridging the GP1 and GP2 subunits. Complementary biochemical analyses indicate that antibody 25.10C, which is broadly specific, neutralizes by inhibiting binding of the endosomal receptor LAMP1 and also by blocking membrane fusion. The other GPC-A antibody, 36.1F, which is lineage-specific, prevents LAMP1 association only. These data illuminate a site of vulnerability on LASV GP and will guide efforts to elicit broadly reactive therapeutics and vaccines.
History
DepositionSep 17, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 1, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 15, 2022Group: 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 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: 25.10C-FNQI Fab Heavy Chain
L: 25.10C-FNQI Fab Light Chain
h: 25.10C-FNQI Fab Heavy Chain
l: 25.10C-FNQI Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)95,0124
Polymers95,0124
Non-polymers00
Water1,71195
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8980 Å2
ΔGint-44 kcal/mol
Surface area36620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.600, 72.718, 90.014
Angle α, β, γ (deg.)90.000, 113.267, 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 25.10C-FNQI Fab Heavy Chain


Mass: 24578.650 Da / Num. of mol.: 2
Mutation: Residues 112-116 (SSAST) of 25.10C Fab heavy chain mutated to FNQI (residues 120-123 in the numbering used in this construct)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody 25.10C-FNQI Fab Light Chain


Mass: 22927.467 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 95 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.33 Å3/Da / Density % sol: 47.21 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion
Details: 0.1 M MES/sodium hydroxide pH 6.0, 40% (v/v) PEG 400, and 5% (w/v) PEG 3000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.03317 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 22, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03317 Å / Relative weight: 1
ReflectionResolution: 2.566→65.78 Å / Num. obs: 27076 / % possible obs: 98.8 % / Redundancy: 3.3 % / CC1/2: 0.995 / Net I/σ(I): 5.4
Reflection shellResolution: 2.566→2.61 Å / Num. unique obs: 1338 / CC1/2: 0.564

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ULU

3ulu


Resolution: 2.57→65.78 Å / Cross valid method: FREE R-VALUE / σ(F): 37.72 / Phase error: 41.138
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2627 1370 5.06 %
Rwork0.2204 25695 -
obs0.2246 27065 98.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 63.31 Å2
Refinement stepCycle: LAST / Resolution: 2.57→65.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6359 0 0 95 6454
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00296498
X-RAY DIFFRACTIONf_angle_d0.60598839
X-RAY DIFFRACTIONf_chiral_restr0.04271002
X-RAY DIFFRACTIONf_plane_restr0.00391138
X-RAY DIFFRACTIONf_dihedral_angle_d12.07392309
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.57-2.660.39221230.32172583X-RAY DIFFRACTION94.93
2.66-2.760.35181570.32642557X-RAY DIFFRACTION93.73
2.76-2.890.34861290.29532573X-RAY DIFFRACTION94.98
2.89-3.040.29921300.28742564X-RAY DIFFRACTION94.72
3.04-3.230.27881290.26272601X-RAY DIFFRACTION94.65
3.23-3.480.26371350.25072548X-RAY DIFFRACTION93.57
3.48-3.830.27651650.22892519X-RAY DIFFRACTION92.3
3.83-4.390.22131410.18342550X-RAY DIFFRACTION92.86
4.39-5.530.20881010.16532612X-RAY DIFFRACTION94.36
5.53-65.780.26381440.2042604X-RAY DIFFRACTION92.44
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)
12.2563726010.4657188699062.413114999730.80294781920.1572356688732.9652669170.1087525564620.434440619559-0.3266172586040.06321420963540.108920234517-0.06099389986380.08942546847730.772332069977-0.2221955077040.3136852806270.06687914111830.01254497689610.811927888134-0.04286896663150.307636145546-43.4323697151-20.422043508422.3426036076
23.621108400621.109069495461.222562409371.417819818090.1926123512510.892838137581-0.01746883479340.106034751308-0.01218269535650.03010009795120.1069800670250.2295291788160.2186495536660.286075506444-0.06079438896530.392211808133-0.00101616456291-0.04379919230680.606268449028-0.008161681324890.33577511767-48.8806653198-25.915728474646.9124526172
31.8752755910.0909170678067-1.298605141180.587166328472-0.4222220737732.196565568370.07933004486870.0253462791279-0.0854262375074-0.0269207265905-0.1274824939270.115811065659-0.1721572617860.3106694141760.02129793299030.3144294044370.00159533632338-0.08975810662020.7752317045850.004781973147010.363450472994-42.6749165823-17.106628029217.1420903659
42.91699569076-0.716186479613-0.9015744653310.8941299340330.07587990339010.155087203743-0.126860646370.08373687976630.0226791598963-0.2274720499130.08798128836690.1020920460950.01950047178490.3368546207980.09348500419350.4050929743760.058483354819-0.0822459555170.749450988237-0.03406485995130.256223102015-49.4079830707-11.2929898757-7.06198241816
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'H' and resid 3 through 221)HA3 - 2211 - 212
22(chain 'L' and resid 1 through 209)LB1 - 2091 - 209
33(chain 'h' and resid 3 through 217)hC3 - 2171 - 208
44(chain 'l' and resid 1 through 209)lD1 - 2091 - 209

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