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Entry
Database: PDB / ID: 7uyl
Title850 Fab
Components
  • 850 Fab Heavy Chain
  • 850 Fab Light Chain
  • VHH nanobody
KeywordsANTIMICROBIAL PROTEIN / IMMUNE SYSTEM / antibody / malaria / Plasmodium falciparum / circumsporozoite protein
Biological speciesMus musculus (house mouse)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsKucharska, I. / Prieto, K. / Julien, J.P.
Funding support Canada, United States, 6items
OrganizationGrant numberCountry
Ontario Early Researcher Awards Canada
Canada Foundation for Innovation Canada
Ontario Research Fund Canada
Canada Research Chairs Canada
Bill & Melinda Gates FoundationINV-008866 United States
CIFAR Azrieli Global Scholars Canada
CitationJournal: PLoS Pathog / Year: 2022
Title: High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire.
Authors: Iga Kucharska / Špela Binter / Rajagopal Murugan / Stephen W Scally / Julia Ludwig / Katherine Prieto / Elaine Thai / Giulia Costa / Kan Li / Gillian Q Horn / Yevel Flores-Garcia / ...Authors: Iga Kucharska / Špela Binter / Rajagopal Murugan / Stephen W Scally / Julia Ludwig / Katherine Prieto / Elaine Thai / Giulia Costa / Kan Li / Gillian Q Horn / Yevel Flores-Garcia / Alexandre Bosch / Taylor Sicard / John L Rubinstein / Fidel Zavala / S Moses Dennison / Georgia D Tomaras / Elena A Levashina / Paul Kellam / Hedda Wardemann / Jean-Philippe Julien /
Abstract: Antibodies targeting the human malaria parasite Plasmodium falciparum circumsporozoite protein (PfCSP) can prevent infection and disease. PfCSP contains multiple central repeating NANP motifs; some ...Antibodies targeting the human malaria parasite Plasmodium falciparum circumsporozoite protein (PfCSP) can prevent infection and disease. PfCSP contains multiple central repeating NANP motifs; some of the most potent anti-infective antibodies against malaria bind to these repeats. Multiple antibodies can bind the repeating epitopes concurrently by engaging into homotypic Fab-Fab interactions, which results in the ordering of the otherwise largely disordered central repeat into a spiral. Here, we characterize IGHV3-33/IGKV1-5-encoded monoclonal antibody (mAb) 850 elicited by immunization of transgenic mice with human immunoglobulin loci. mAb 850 binds repeating NANP motifs with picomolar affinity, potently inhibits Plasmodium falciparum (Pf) in vitro and, when passively administered in a mouse challenge model, reduces liver burden to a similar extent as some of the most potent anti-PfCSP mAbs yet described. Like other IGHV3-33/IGKV1-5-encoded anti-NANP antibodies, mAb 850 primarily utilizes its HCDR3 and germline-encoded aromatic residues to recognize its core NANP motif. Biophysical and cryo-electron microscopy analyses reveal that up to 19 copies of Fab 850 can bind the PfCSP repeat simultaneously, and extensive homotypic interactions are observed between densely-packed PfCSP-bound Fabs to indirectly improve affinity to the antigen. Together, our study expands on the molecular understanding of repeat-induced homotypic interactions in the B cell response against PfCSP for potently protective mAbs against Pf infection.
History
DepositionMay 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 14, 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 / _citation_author.identifier_ORCID / _citation_author.name
Revision 2.0Dec 21, 2022Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Non-polymer description / Polymer sequence / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / entity / entity_poly / entity_poly_seq / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / pdbx_validate_torsion / struct_conf / struct_sheet_range
Item: _atom_site.auth_comp_id / _atom_site.label_comp_id ..._atom_site.auth_comp_id / _atom_site.label_comp_id / _atom_site_anisotrop.pdbx_auth_comp_id / _atom_site_anisotrop.pdbx_label_comp_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _entity.formula_weight / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_poly_seq.mon_id / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_struct_sheet_hbond.range_1_auth_comp_id / _pdbx_struct_sheet_hbond.range_1_label_comp_id / _pdbx_struct_sheet_hbond.range_2_auth_comp_id / _pdbx_struct_sheet_hbond.range_2_label_comp_id / _pdbx_unobs_or_zero_occ_residues.auth_comp_id / _pdbx_unobs_or_zero_occ_residues.label_comp_id / _pdbx_validate_torsion.auth_comp_id / _struct_conf.beg_auth_comp_id / _struct_conf.beg_label_comp_id / _struct_conf.end_auth_comp_id / _struct_conf.end_label_comp_id / _struct_sheet_range.beg_auth_comp_id / _struct_sheet_range.beg_label_comp_id / _struct_sheet_range.end_auth_comp_id / _struct_sheet_range.end_label_comp_id
Revision 2.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: 850 Fab Heavy Chain
L: 850 Fab Light Chain
K: VHH nanobody
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,4057
Polymers59,0363
Non-polymers3684
Water6,990388
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)137.180, 137.180, 63.770
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number80
Space group name H-MI41

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Components

#1: Antibody 850 Fab Heavy Chain


Mass: 24234.037 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#2: Antibody 850 Fab Light Chain


Mass: 23476.045 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Antibody VHH nanobody


Mass: 11326.253 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Homo sapiens (human)
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 388 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.59 Å3/Da / Density % sol: 52.42 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 85 mM Tris pH 8.5, 170 mM sodium acetate, 25.5% (w/v) polyethylene glycol 4000, 15% glycerol

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033167 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 7, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033167 Å / Relative weight: 1
ReflectionResolution: 2→37.16 Å / Num. obs: 40192 / % possible obs: 100 % / Redundancy: 7.93 % / CC1/2: 0.995 / Net I/av σ(I): 1.95 / Net I/σ(I): 8.55
Reflection shellResolution: 2→2.1 Å / Redundancy: 8 % / Mean I/σ(I) obs: 1.95 / Num. unique obs: 5428 / CC1/2: 0.706 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XPREPdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6D01

6d01


Resolution: 2→37.16 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2123 1991 4.96 %
Rwork0.1739 --
obs0.1758 40174 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2→37.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4066 0 24 388 4478
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044423
X-RAY DIFFRACTIONf_angle_d0.7086017
X-RAY DIFFRACTIONf_dihedral_angle_d11.8181580
X-RAY DIFFRACTIONf_chiral_restr0.047665
X-RAY DIFFRACTIONf_plane_restr0.005770
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.050.30441420.24042713X-RAY DIFFRACTION100
2.05-2.110.27051390.23392689X-RAY DIFFRACTION100
2.11-2.170.22921440.21272718X-RAY DIFFRACTION100
2.17-2.240.2631410.20412717X-RAY DIFFRACTION100
2.24-2.320.26561390.21122719X-RAY DIFFRACTION100
2.32-2.410.2631380.20732708X-RAY DIFFRACTION100
2.41-2.520.251450.21342712X-RAY DIFFRACTION100
2.52-2.650.25151420.18952703X-RAY DIFFRACTION100
2.65-2.820.2371410.19232722X-RAY DIFFRACTION100
2.82-3.040.21661450.17242743X-RAY DIFFRACTION100
3.04-3.340.21151430.17022730X-RAY DIFFRACTION100
3.34-3.820.18821410.14332732X-RAY DIFFRACTION100
3.83-4.820.15331440.1292766X-RAY DIFFRACTION100
4.82-37.160.18231470.16452811X-RAY DIFFRACTION100
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)
17.9368-2.3225-3.98143.90111.35965.2664-0.3601-0.3296-0.50530.55470.160.26410.4285-0.01360.23920.2139-0.0778-0.02750.20880.03310.1318-15.859-51.97748.148
23.9143-2.2212-5.50454.71653.83377.886-0.0751-0.6056-0.08450.23070.2342-0.4498-0.09840.25710.04850.18-0.0254-0.03820.24340.00690.1461-8.926-51.55946.967
36.0316-0.08361.77014.7065-4.8656.5071-0.3554-0.2626-1.4126-0.01120.1947-0.74830.51640.06250.28060.23030.0389-0.01710.36520.09970.46292.748-54.92737.558
43.5274.831-1.2246.6477-1.57130.7801-0.33870.3822-0.2884-0.31750.2071-0.02160.25970.04350.11830.1786-0.01790.02120.249-0.03610.14-18.451-53.75235.975
50.4661-0.0957-1.68716.709-0.06276.13140.24190.0220.13850.1299-0.1273-0.1023-0.19220.2327-0.05210.14120.0025-0.00540.13920.01780.0912-6.965-44.78934.046
62.738-1.74761.25433.887-0.47653.7944-0.15040.13040.26610.2399-0.089-0.2866-0.10090.34340.22250.1794-0.03890.00430.18640.04420.186-9.626-44.70141.988
71.31940.4283-2.39131.2339-0.05724.8387-0.124-0.0285-0.22280.0138-0.03190.01130.2063-0.00860.12870.12790.0068-0.04470.17610.03090.1571-12.814-50.43436.539
86.3774-1.4678-4.31834.16371.10022.9272-0.3692-0.1436-0.5306-0.30590.0446-0.10431.0940.13810.42070.30610.04130.01320.23820.05610.2745-9.191-59.96336.139
95.6429-2.37724.19582.30320.29248.4667-0.82750.0368-0.33920.99430.08470.79140.1074-0.67570.73010.2636-0.02740.08810.2113-0.03180.2636-24.748-50.91148.279
102.63262.53280.75288.82282.57353.1134-0.09070.31390.2373-0.40340.11270.1497-0.326-0.0041-0.00080.1765-0.020.01970.22410.05530.188811.4-21.554-2
114.40551.086-1.4684.1403-0.72074.33950.00130.1705-0.31960.1051-0.0219-0.3883-0.03440.2830.02620.1539-0.0206-0.02430.1849-0.04350.232519.622-24.7963.338
122.91631.2371-0.43065.54012.14814.91530.07840.058-0.0327-0.0325-0.0243-0.5118-0.1227-0.0257-0.11790.1010.00220.00350.17920.04010.258816.537-23.3475.191
131.45750.71460.30451.07460.44530.3662-0.08760.1096-0.09780.00930.1129-0.118-0.0256-0.0461-0.02150.188-0.00130.01950.2270.00620.1581-9.991-43.0222.068
148.41753.1607-6.32422.4349-2.89297.5184-0.12020.505-0.0022-0.14530.22480.08150.0274-0.4759-0.09940.2146-0.0059-0.01090.25510.00120.1466-19.154-44.626-4.918
152.51790.7851.05952.2975-0.58930.9211-0.047-0.1236-0.41750.0734-0.057-0.27290.06860.14970.08490.1691-0.0009-0.03050.18910.0050.20076.404-32.72826.094
164.32820.1751-1.38741.4075-0.26192.68770.0138-0.12870.13590.09420.0107-0.1431-0.11430.1028-0.0190.1621-0.0098-0.02490.1298-0.02280.19439.822-24.34522.753
171.25930.73660.52411.91590.84812.1403-0.0380.0833-0.1759-0.19910.0226-0.13260.1837-0.1002-0.02350.2075-0.010.02760.14390.01840.1688-10.701-50.212.996
182.19130.2475-0.27841.54991.47123.1515-0.087-0.0721-0.26-0.0610.2255-0.21220.28250.3063-0.13350.21570.03930.01570.23650.0410.2014-7.517-49.41613.63
191.6048-0.40050.04570.68050.54960.6528-0.11320.0689-0.4164-0.23460.0562-0.35620.77470.0216-0.01880.5254-0.00210.11590.1745-0.00110.2984-8.924-61.4096.912
201.91740.50390.75694.88994.55055.8614-0.1638-0.0584-0.1694-0.1191-0.01180.16110.4485-0.26480.19120.2767-0.05520.02320.11250.03130.2096-14.464-59.20117.814
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN K AND RESID 2:17 )K2 - 17
2X-RAY DIFFRACTION2( CHAIN K AND RESID 18:25 )K18 - 25
3X-RAY DIFFRACTION3( CHAIN K AND RESID 26:33 )K26 - 33
4X-RAY DIFFRACTION4( CHAIN K AND RESID 34:45 )K34 - 45
5X-RAY DIFFRACTION5( CHAIN K AND RESID 46:60 )K46 - 60
6X-RAY DIFFRACTION6( CHAIN K AND RESID 61:83 )K61 - 83
7X-RAY DIFFRACTION7( CHAIN K AND RESID 84:107 )K84 - 107
8X-RAY DIFFRACTION8( CHAIN K AND RESID 108:114 )K108 - 114
9X-RAY DIFFRACTION9( CHAIN K AND RESID 115:121 )K115 - 121
10X-RAY DIFFRACTION10( CHAIN H AND RESID 1:33 )H1 - 33
11X-RAY DIFFRACTION11( CHAIN H AND RESID 34:75 )H34 - 75
12X-RAY DIFFRACTION12( CHAIN H AND RESID 76:100 )H76 - 100
13X-RAY DIFFRACTION13( CHAIN H AND RESID 101:188 )H101 - 188
14X-RAY DIFFRACTION14( CHAIN H AND RESID 189:214 )H189 - 214
15X-RAY DIFFRACTION15( CHAIN L AND RESID 1:18 )L1 - 18
16X-RAY DIFFRACTION16( CHAIN L AND RESID 19:101 )L19 - 101
17X-RAY DIFFRACTION17( CHAIN L AND RESID 102:149 )L102 - 149
18X-RAY DIFFRACTION18( CHAIN L AND RESID 150:173 )L150 - 173
19X-RAY DIFFRACTION19( CHAIN L AND RESID 174:197 )L174 - 197
20X-RAY DIFFRACTION20( CHAIN L AND RESID 198:212 )L198 - 212

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