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- PDB-6pbw: Crystal structure of Fab667 complex -

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Basic information

Entry
Database: PDB / ID: 6pbw
TitleCrystal structure of Fab667 complex
Components
  • Fab667 heavy chain
  • Fab667 light chain
  • NPNANPNANPNA peptide
KeywordsIMMUNE SYSTEM / Fab fragment
Function / homology
Function and homology information


host cell surface binding / symbiont entry into host / entry into host cell by a symbiont-containing vacuole / heparan sulfate proteoglycan binding / 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
TRIETHYLENE GLYCOL / Circumsporozoite protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Plasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.058 Å
AuthorsOyen, D. / Wilson, I.A.
CitationJournal: PLoS Pathog / Year: 2020
Title: Structure and mechanism of monoclonal antibody binding to the junctional epitope of Plasmodium falciparum circumsporozoite protein.
Authors: David Oyen / Jonathan L Torres / Phillip C Aoto / Yevel Flores-Garcia / Špela Binter / Tossapol Pholcharee / Sean Carroll / Sini Reponen / Rachael Wash / Qi Liang / Franck Lemiale / Emily ...Authors: David Oyen / Jonathan L Torres / Phillip C Aoto / Yevel Flores-Garcia / Špela Binter / Tossapol Pholcharee / Sean Carroll / Sini Reponen / Rachael Wash / Qi Liang / Franck Lemiale / Emily Locke / Allan Bradley / C Richter King / Daniel Emerling / Paul Kellam / Fidel Zavala / Andrew B Ward / Ian A Wilson /
Abstract: Lasting protection has long been a goal for malaria vaccines. The major surface antigen on Plasmodium falciparum sporozoites, the circumsporozoite protein (PfCSP), has been an attractive target for ...Lasting protection has long been a goal for malaria vaccines. The major surface antigen on Plasmodium falciparum sporozoites, the circumsporozoite protein (PfCSP), has been an attractive target for vaccine development and most protective antibodies studied to date interact with the central NANP repeat region of PfCSP. However, it remains unclear what structural and functional characteristics correlate with better protection by one antibody over another. Binding to the junctional region between the N-terminal domain and central NANP repeats has been proposed to result in superior protection: this region initiates with the only NPDP sequence followed immediately by NANP. Here, we isolated antibodies in Kymab mice immunized with full-length recombinant PfCSP and two protective antibodies were selected for further study with reactivity against the junctional region. X-ray and EM structures of two monoclonal antibodies, mAb667 and mAb668, shed light on their differential affinity and specificity for the junctional region. Importantly, these antibodies also bind to the NANP repeat region with equal or better affinity. A comparison with an NANP-only binding antibody (mAb317) revealed roughly similar but statistically distinct levels of protection against sporozoite challenge in mouse liver burden models, suggesting that junctional antibody protection might relate to the ability to also cross-react with the NANP repeat region. Our findings indicate that additional efforts are necessary to isolate a true junctional antibody with no or much reduced affinity to the NANP region to elucidate the role of the junctional epitope in protection.
History
DepositionJun 14, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2020Group: 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 1.2Apr 3, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Fab667 light chain
D: Fab667 heavy chain
E: NPNANPNANPNA peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,3265
Polymers49,0833
Non-polymers2422
Water2,990166
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5350 Å2
ΔGint-22 kcal/mol
Surface area19840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.397, 70.397, 186.485
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

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Protein/peptide , 1 types, 1 molecules E

#3: Protein/peptide NPNANPNANPNA peptide


Mass: 1231.255 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Plasmodium falciparum 3D7 (eukaryote) / References: UniProt: Q7K740*PLUS

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Antibody , 2 types, 2 molecules CD

#1: Antibody Fab667 light chain


Mass: 22855.205 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 Fab667 heavy chain


Mass: 24997.020 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)

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Non-polymers , 3 types, 168 molecules

#4: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 166 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.72 Å3/Da / Density % sol: 54.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 20% glycerol 25% PEG1500

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 32790 / % possible obs: 97.7 % / Redundancy: 9.8 % / CC1/2: 0.907 / Rpim(I) all: 0.054 / Rsym value: 0.171 / Net I/σ(I): 12
Reflection shellResolution: 2.05→2.09 Å / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1304 / CC1/2: 0.706 / Rpim(I) all: 0.432 / Rsym value: 0.759 / % possible all: 78.8

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Processing

Software
NameVersionClassification
PHENIX(1.16_3549: ???)refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: homology model

Resolution: 2.058→43.526 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 29.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2584 1605 4.91 %
Rwork0.202 --
obs0.2046 32709 95.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.058→43.526 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3314 0 16 166 3496
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023418
X-RAY DIFFRACTIONf_angle_d0.5244657
X-RAY DIFFRACTIONf_dihedral_angle_d10.8192385
X-RAY DIFFRACTIONf_chiral_restr0.042520
X-RAY DIFFRACTIONf_plane_restr0.005594
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.058-2.12440.3434960.30971860X-RAY DIFFRACTION64
2.1244-2.20030.33371400.2972655X-RAY DIFFRACTION92
2.2003-2.28840.2961530.29062874X-RAY DIFFRACTION99
2.2884-2.39260.33691560.2652884X-RAY DIFFRACTION100
2.3926-2.51870.29951640.2632912X-RAY DIFFRACTION100
2.5187-2.67650.32341440.25262908X-RAY DIFFRACTION100
2.6765-2.88310.28451570.23682934X-RAY DIFFRACTION100
2.8831-3.17320.29331640.23092934X-RAY DIFFRACTION100
3.1732-3.63210.24991360.19952975X-RAY DIFFRACTION100
3.6321-4.57530.24611410.16363019X-RAY DIFFRACTION100
4.5753-43.5260.20161540.16573149X-RAY DIFFRACTION99
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)
14.096-1.2783-1.49255.59130.03255.7763-0.17350.0080.39480.20930.1492-0.1438-1.1417-0.0676-0.00120.6062-0.0134-0.04180.31810.04290.3248-13.1276-12.646722.9633
23.8115-1.9021-2.15541.93610.72056.4481-0.32910.1378-0.23110.15970.07690.1142-0.8283-0.24370.1020.6316-0.0379-0.02160.32380.0890.439-11.1636-16.109125.9733
32.47411.166-2.88790.6101-1.71424.94150.56610.22010.6361-0.33980.17060.0901-1.1047-1.1407-0.78380.8220.2509-0.00280.4513-0.07920.5354-22.7471-10.082341.8729
44.507-0.79011.32226.7364-2.90876.68960.16320.0060.0022-0.1283-0.2685-0.44050.34820.14990.08630.26120.06390.02620.3292-0.03150.2755-15.4304-22.437862.982
55.2238-0.06970.5485.1752-0.23955.0169-0.00680.28980.29780.1123-0.2637-0.3886-0.64860.56750.27820.39650.06610.02570.33080.04560.4104-12.4747-20.313360.6693
65.7177-1.7342.33915.1667-2.68381.741-0.1098-0.32650.35240.32560.0384-0.33550.0988-0.26070.08940.5970.07090.00490.4076-0.01370.399-16.9108-13.555865.968
72.25610.01430.53851.9143-0.23336.5028-0.16030.0268-0.1369-0.01350.1478-0.113-0.2010.48090.00280.3277-0.0330.01960.3653-0.04720.3782-2.1637-33.297227.2662
84.4284-1.20790.22033.53943.17784.3938-0.0770.78820.0153-0.69950.00710.0076-0.328-0.36080.0110.3733-0.11340.0090.41340.02190.3964-7.1101-28.265614.983
90.60980.1837-2.44590.4601-0.15987.5295-0.1106-0.0632-0.0637-0.00590.0671-0.03090.01380.27210.01260.28440.0097-0.01930.3858-0.00610.3501-11.8717-32.111448.1255
107.818-1.5079-3.9042.77810.38435.6218-0.11840.134-0.23620.2423-0.02240.13460.5111-0.2560.13520.36170.0366-0.04220.3255-0.00620.2195-19.634-36.158258.7521
110.8072-1.1492-0.80135.70161.66632.63860.05680.6757-0.0257-1.05370.0502-0.2909-0.27820.1729-0.19060.6476-0.17150.09940.74480.09290.32630.1332-25.683310.6325
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'C' and (resid 2 through 75 )
2X-RAY DIFFRACTION2chain 'C' and (resid 76 through 101 )
3X-RAY DIFFRACTION3chain 'C' and (resid 102 through 113 )
4X-RAY DIFFRACTION4chain 'C' and (resid 114 through 150 )
5X-RAY DIFFRACTION5chain 'C' and (resid 151 through 187 )
6X-RAY DIFFRACTION6chain 'C' and (resid 188 through 208 )
7X-RAY DIFFRACTION7chain 'D' and (resid 1 through 87 )
8X-RAY DIFFRACTION8chain 'D' and (resid 88 through 100G)
9X-RAY DIFFRACTION9chain 'D' and (resid 100H through 145 )
10X-RAY DIFFRACTION10chain 'D' and (resid 146 through 214 )
11X-RAY DIFFRACTION11chain 'E' and (resid 1 through 8 )

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