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- PDB-7uym: 850 Fab in complex with NANPNANPNANP peptide -

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Basic information

Entry
Database: PDB / ID: 7uym
Title850 Fab in complex with NANPNANPNANP peptide
Components
  • 850 Fab Heavy Chain
  • 850 Fab Light Chain
  • Circumsporozoite protein
  • VHH nanobody
KeywordsANTIMICROBIAL PROTEIN / IMMUNE SYSTEM / antibody / malaria / Plasmodium falciparum / circumsporozoite protein
Function / homology
Function and homology information


entry into host cell by a symbiont-containing vacuole / side of membrane / cell surface / plasma membrane / cytoplasm
Similarity search - Function
: / Plasmodium circumsporozoite protein / Thrombospondin type 1 domain / Thrombospondin type-1 (TSP1) repeat superfamily / Thrombospondin type-1 (TSP1) repeat profile. / Thrombospondin type 1 repeats / Thrombospondin type-1 (TSP1) repeat / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Circumsporozoite protein
Similarity search - Component
Biological speciesMus musculus (house mouse)
Lama glama (llama)
Plasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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
Revision 2.2Oct 23, 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: 850 Fab Heavy Chain
K: VHH nanobody
L: 850 Fab Light Chain
P: Circumsporozoite protein


Theoretical massNumber of molelcules
Total (without water)60,2444
Polymers60,2444
Non-polymers00
Water2,810156
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)137.500, 137.500, 63.600
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 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)
#3: 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)
#4: Protein/peptide Circumsporozoite protein / CS


Mass: 1207.210 Da / Num. of mol.: 1 / Fragment: residues 148-159 / Source method: obtained synthetically
Source: (synth.) Plasmodium falciparum (malaria parasite P. falciparum)
References: UniProt: P02893
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 156 / 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: 2.54 Å3/Da / Density % sol: 51.53 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / Details: 0.2 M KCl, 20% (w/v) polyethylene glycol 2250

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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: Feb 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033167 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 30049 / % possible obs: 99.6 % / Redundancy: 7.69 % / CC1/2: 0.996 / Net I/σ(I): 10.62
Reflection shellResolution: 2.2→2.3 Å / Mean I/σ(I) obs: 1.9 / Num. unique obs: 3487 / CC1/2: 0.484 / % possible all: 97.3

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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: 2.2→29.53 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.69 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2155 1506 5.01 %
Rwork0.1687 --
obs0.171 30040 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→29.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4111 0 0 156 4267
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034421
X-RAY DIFFRACTIONf_angle_d0.6326013
X-RAY DIFFRACTIONf_dihedral_angle_d11.8091570
X-RAY DIFFRACTIONf_chiral_restr0.045663
X-RAY DIFFRACTIONf_plane_restr0.005775
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.270.30491380.25712509X-RAY DIFFRACTION96
2.28-2.360.29121310.24052554X-RAY DIFFRACTION100
2.36-2.450.27691390.22572604X-RAY DIFFRACTION100
2.45-2.560.27871340.21192572X-RAY DIFFRACTION100
2.56-2.70.28191360.21432604X-RAY DIFFRACTION100
2.7-2.870.28461380.19692579X-RAY DIFFRACTION100
2.87-3.090.2331330.18762588X-RAY DIFFRACTION100
3.09-3.40.23171380.17652614X-RAY DIFFRACTION100
3.4-3.890.18471390.14712608X-RAY DIFFRACTION100
3.89-4.890.15871380.12452634X-RAY DIFFRACTION100
4.89-29.530.181420.14672668X-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)
11.37622.48471.73028.9792.03862.4341-0.12530.365-0.2856-1.20720.08560.2423-0.4996-0.04380.01310.2929-0.0548-0.00130.50730.00290.30099.284-27.889-4.395
24.06241.10460.08623.27280.41182.1955-0.0910.2078-0.0649-0.11550.0711-0.1515-0.00760.0760.02370.2276-0.02660.01980.2661-0.03670.25617.055-21.7463.87
33.2263-0.4452-1.20357.5874-0.06022.7761-0.21380.4739-0.1618-0.17560.1347-0.0651-0.0486-0.22410.09550.2341-0.05990.01590.3496-0.04540.286919.236-23.553-2.466
42.86143.43551.47055.78862.80483.8668-0.01460.0776-0.4023-0.2837-0.0096-0.48450.2379-0.33280.02130.2553-0.0310.04530.30890.00330.284813.777-31.1451.42
54.16071.72950.15658.7533.89777.2063-0.1107-0.38860.5571-0.1043-0.2596-0.1317-0.5551-0.19740.25570.2206-0.02880.03860.240.07270.258915.027-17.94711.909
64.51870.989-2.37371.4883-0.47583.778-0.08210.1722-0.19530.07440.1175-0.0408-0.0926-0.5169-0.040.288-0.01330.01620.3288-0.01170.21-13.998-45.26-0.343
75.5974-0.5789-1.16524.30850.06520.9018-0.2035-0.2676-0.20360.26270.1022-0.13860.11820.12740.08150.27410.0185-0.04830.3015-0.00660.22656.286-32.84826.029
85.41840.0746-1.60164.1892-0.62754.31660.0621-0.10390.38140.11770.0436-0.0507-0.3181-0.0519-0.09640.2683-0.0065-0.0020.2245-0.03080.258110.023-22.90122.217
94.12622.2266-0.95671.5997-0.76020.75680.0589-0.1820.14080.1411-0.0708-0.0399-0.09770.04740.02440.26250.0263-0.02140.2773-0.00130.27845.533-29.0323.429
102.5860.4967-0.84614.82562.61937.1247-0.2810.3672-0.2728-0.38590.1388-0.0940.2592-0.10690.11720.28-0.06570.04880.2680.03980.2873-11.1-54.2389.166
113.01930.0616-1.34865.50651.9962.7964-0.2263-0.2819-0.35240.18140.1688-0.04130.23790.10820.0230.3130.0178-0.02390.31160.05440.2422-7.466-48.53213.66
121.92280.1416-0.91882.56660.70062.6236-0.32870.3201-0.3725-0.45930.0634-0.17930.7682-0.28950.20470.5128-0.08740.09010.2553-0.03950.32-11.001-61.16310.602
136.7427-1.93030.74494.3748-0.20851.47470.0248-0.6092-0.17680.05920.18230.19330.3214-0.0383-0.16390.4401-0.04460.02910.42290.02610.2156-13.444-51.71647.538
145.01611.27961.95196.3786-2.94353.8993-0.2704-0.9419-1.34040.3014-0.0133-1.21362.0670.47260.33460.56290.11850.00840.61720.13870.61322.958-54.62637.407
154.24945.1001-2.14576.6352-1.60382.8957-0.59550.7475-1.1366-0.42670.363-0.19190.6076-0.12020.2470.3798-0.04980.08070.4152-0.04960.2966-18.458-53.87435.834
162.7959-1.0894-2.60515.2953-0.70595.54320.32760.06250.57310.092-0.063-0.3461-0.03880.1867-0.25020.2156-0.0268-0.00110.2365-0.02070.2145-7.221-44.78533.813
179.8443-2.45391.38654.29240.49192.92140.1010.06810.19690.2108-0.1666-0.25580.27470.2760.08620.3063-0.03610.00760.32570.00810.2418-9.361-44.8342.137
185.7388-0.676-4.4281.46471.6185.42960.06030.4007-0.31550.0673-0.2188-0.03060.0803-0.28940.16180.2922-0.0058-0.04090.27890.04290.2759-12.727-50.37936.357
194.92443.1479-5.44112.5529-2.90686.6088-0.5461-0.6891-0.1348-0.12080.0538-0.53541.70150.7640.65790.53450.06460.06590.4430.00860.5822-9.155-59.97935.986
209.6376-4.7027-2.28436.10130.82333.1846-0.44770.2494-0.3023-0.19420.14950.3678-0.0652-0.14260.31520.5269-0.13180.01730.4796-0.03550.3243-23.439-51.58447.363
212.55312.9138-3.79313.3311-4.46578.48520.0887-0.2060.70870.3955-1.0864-1.6333-0.38831.16450.90270.3314-0.12730.01660.3760.04150.597125.418-14.9911.568
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN H AND RESID 1:17 )H1 - 17
2X-RAY DIFFRACTION2( CHAIN H AND RESID 18:59 )H18 - 59
3X-RAY DIFFRACTION3( CHAIN H AND RESID 60:82 )H60 - 82
4X-RAY DIFFRACTION4( CHAIN H AND RESID 83:95 )H83 - 95
5X-RAY DIFFRACTION5( CHAIN H AND RESID 96:109 )H96 - 109
6X-RAY DIFFRACTION6( CHAIN H AND RESID 110:214 )H110 - 214
7X-RAY DIFFRACTION7( CHAIN L AND RESID 1:18 )L1 - 18
8X-RAY DIFFRACTION8( CHAIN L AND RESID 19:61 )L19 - 61
9X-RAY DIFFRACTION9( CHAIN L AND RESID 62:112 )L62 - 112
10X-RAY DIFFRACTION10( CHAIN L AND RESID 113:149 )L113 - 149
11X-RAY DIFFRACTION11( CHAIN L AND RESID 150:173 )L150 - 173
12X-RAY DIFFRACTION12( CHAIN L AND RESID 174:212 )L174 - 212
13X-RAY DIFFRACTION13( CHAIN K AND RESID 2:25 )K2 - 25
14X-RAY DIFFRACTION14( CHAIN K AND RESID 26:33 )K26 - 33
15X-RAY DIFFRACTION15( CHAIN K AND RESID 34:45 )K34 - 45
16X-RAY DIFFRACTION16( CHAIN K AND RESID 46:60 )K46 - 60
17X-RAY DIFFRACTION17( CHAIN K AND RESID 61:83 )K61 - 83
18X-RAY DIFFRACTION18( CHAIN K AND RESID 84:107 )K84 - 107
19X-RAY DIFFRACTION19( CHAIN K AND RESID 108:114 )K108 - 114
20X-RAY DIFFRACTION20( CHAIN K AND RESID 115:120 )K115 - 120
21X-RAY DIFFRACTION21( CHAIN P AND RESID 2:11 )P2 - 11

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