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- PDB-6pbv: Crystal structure of Fab668 complex -

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Basic information

Entry
Database: PDB / ID: 6pbv
TitleCrystal structure of Fab668 complex
Components
  • Fab668 heavy chain
  • Fab668 light chain
  • Junctional 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
Circumsporozoite protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Plasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.566 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
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fab668 light chain
B: Fab668 heavy chain
C: Fab668 light chain
D: Fab668 heavy chain
G: Junctional peptide
I: Junctional peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,7118
Polymers97,5866
Non-polymers1242
Water14,016778
1
A: Fab668 light chain
B: Fab668 heavy chain
G: Junctional peptide


Theoretical massNumber of molelcules
Total (without water)48,7933
Polymers48,7933
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4400 Å2
ΔGint-26 kcal/mol
Surface area19800 Å2
MethodPISA
2
C: Fab668 light chain
D: Fab668 heavy chain
I: Junctional peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,9175
Polymers48,7933
Non-polymers1242
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4760 Å2
ΔGint-24 kcal/mol
Surface area20050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.065, 60.127, 76.338
Angle α, β, γ (deg.)72.43, 68.07, 83.58
Int Tables number1
Space group name H-MP1

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Components

#1: Antibody Fab668 light chain


Mass: 22737.088 Da / Num. of mol.: 2
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 Fab668 heavy chain


Mass: 24596.588 Da / Num. of mol.: 2
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: Protein/peptide Junctional peptide


Mass: 1459.520 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Plasmodium falciparum 3D7 (eukaryote) / References: UniProt: Q7K740*PLUS
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 778 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: 2.42 Å3/Da / Density % sol: 49.07 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 0.1M HEPES (pH 6.96) 8% Ethylene Glycol 16% PEG10000

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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 PILATUS 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: 1.566→50 Å / Num. obs: 111126 / % possible obs: 86.8 % / Redundancy: 7 % / CC1/2: 0.907 / Rpim(I) all: 0.072 / Rsym value: 0.181 / Net I/σ(I): 23.3
Reflection shellResolution: 1.566→1.6 Å / Mean I/σ(I) obs: 2.2 / Num. unique obs: 5151 / CC1/2: 0.703 / Rpim(I) all: 0.389 / Rsym value: 0.773

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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: 1.566→35.051 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 21.22 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2117 5483 4.94 %
Rwork0.177 --
obs0.1787 111082 86.47 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.566→35.051 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6592 0 8 778 7378
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0146950
X-RAY DIFFRACTIONf_angle_d1.3939542
X-RAY DIFFRACTIONf_dihedral_angle_d10.2815521
X-RAY DIFFRACTIONf_chiral_restr0.0831086
X-RAY DIFFRACTIONf_plane_restr0.011225
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5664-1.58420.25921540.22022723X-RAY DIFFRACTION67
1.5842-1.60280.25071770.22193649X-RAY DIFFRACTION88
1.6028-1.62240.25141710.20563593X-RAY DIFFRACTION89
1.6224-1.64290.23751800.20353571X-RAY DIFFRACTION89
1.6429-1.66450.23041830.20123626X-RAY DIFFRACTION88
1.6645-1.68730.25771870.20243531X-RAY DIFFRACTION88
1.6873-1.71140.24381960.20273529X-RAY DIFFRACTION86
1.7114-1.7370.24272080.18933484X-RAY DIFFRACTION87
1.737-1.76410.22321770.18613510X-RAY DIFFRACTION86
1.7641-1.7930.24252010.18713407X-RAY DIFFRACTION85
1.793-1.8240.20381930.19133414X-RAY DIFFRACTION83
1.824-1.85710.2291490.19513210X-RAY DIFFRACTION79
1.8571-1.89280.24591590.19523257X-RAY DIFFRACTION80
1.8928-1.93150.23011960.18513698X-RAY DIFFRACTION90
1.9315-1.97350.2241940.18073637X-RAY DIFFRACTION90
1.9735-2.01940.23541930.18413661X-RAY DIFFRACTION89
2.0194-2.06990.22842010.18123620X-RAY DIFFRACTION89
2.0699-2.12580.21662040.1813586X-RAY DIFFRACTION89
2.1258-2.18840.25441740.17733607X-RAY DIFFRACTION89
2.1884-2.2590.22941770.18983555X-RAY DIFFRACTION87
2.259-2.33970.21331730.18023382X-RAY DIFFRACTION83
2.3397-2.43340.23861580.17673295X-RAY DIFFRACTION81
2.4334-2.54410.21491690.17663826X-RAY DIFFRACTION92
2.5441-2.67820.20322110.17983668X-RAY DIFFRACTION91
2.6782-2.84590.23941930.18593703X-RAY DIFFRACTION91
2.8459-3.06550.20831880.17923663X-RAY DIFFRACTION90
3.0655-3.37380.19551770.17793385X-RAY DIFFRACTION83
3.3738-3.86140.19631980.16573471X-RAY DIFFRACTION86
3.8614-4.86290.16141750.14953772X-RAY DIFFRACTION92
4.8629-35.0510.18621670.16353566X-RAY DIFFRACTION87
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)
12.61820.6528-1.32613.6655-0.20742.61580.0403-0.0841-0.04480.0937-0.1261-0.21850.00560.17420.05290.09170.0128-0.00790.14250.02240.137411.012712.3435-26.3916
20.9862-0.4053-0.75862.27681.41151.27170.16660.02730.1738-0.0964-0.0823-0.1046-0.21670.1103-0.08020.11960.00330.01540.13340.01970.14347.11918.1136-22.3078
32.4622-0.0662-1.99492.1058-0.54513.3691-0.0586-0.0793-0.0103-0.0558-0.0808-0.21720.17690.04130.13630.1322-0.0115-0.00660.1066-0.00110.1431-5.357437.7002-0.8155
42.3981-2.5824-1.90935.63684.07443.060.4681-0.11530.4661-0.2115-0.1218-0.8232-0.60850.388-0.4260.1812-0.0312-0.01010.20550.00870.29010.577145.2486-0.3318
51.7061-0.2907-0.30641.76191.21312.11920.05670.0274-0.0280.14920.04070.21550.2979-0.5096-0.06280.2291-0.02330.05620.1878-0.00180.2045-12.64534.033-14.5311
62.96560.7919-0.01354.0197-0.15951.7099-0.0311-0.01320.08070.1059-0.0360.1719-0.0655-0.00540.05360.14060.01220.03140.0840.00980.0827-1.18682.7572-17.1456
74.73881.64591.85877.05451.63435.6210.066-0.2758-0.37030.53930.1021-0.33790.33930.1319-0.16120.22220.03250.00260.09260.05160.12130.7984-5.9323-12.6205
83.0545-1.43421.27643.6647-0.27538.05-0.2302-0.1469-0.02750.5052-0.05240.42070.1064-0.33860.1920.2593-0.01750.07510.1360.01940.1766-8.9013-4.2701-13.2281
92.1573-0.3809-1.83472.9925-0.01373.58150.033-0.25940.00960.5720.0194-0.1330.05990.1491-0.08630.2098-0.00010.00080.129-0.00140.1466-4.36686.2694-10.8778
101.11490.25760.2842.73290.36891.9504-0.12420.1626-0.1721-0.0826-0.0639-0.21240.34840.08260.16440.20940.00770.05850.11180.02760.1667-0.13230.4941-23.1291
112.7834-1.98080.00822.45240.75242.0233-0.2328-0.09160.01210.26720.16760.2219-0.12430.02750.10.1956-0.0262-0.00930.1807-0.02620.0903-17.656831.15320.6678
122.66440.4032-0.53813.5195-4.40435.59090.00090.08470.44470.4586-0.19410.1339-0.52320.22690.21940.1644-0.0347-0.04610.1504-0.00430.1822-16.260936.4001-3.2527
130.7338-2.32221.55448.9428-4.65363.59390.11780.3117-0.1125-0.6107-0.22120.09150.3180.00390.11130.2243-0.01550.00620.2571-0.02270.1578-20.636729.2552-8.4366
144.1264-0.3296-0.51074.4211-0.60320.59520.00010.52430.0464-0.4815-0.1624-0.32910.11240.26110.19770.2042-0.04660.04050.1993-0.04850.1432-13.017531.7149-7.1399
153.4423-0.59760.40188.3086-3.86074.4953-0.3410.34860.5205-0.02450.1694-0.0762-0.5446-0.1820.09890.3212-0.0144-0.0580.20880.00960.1586-16.032240.2455-8.1603
164.5318-1.7270.73157.0562-4.62055.3398-0.12560.15420.1651-0.4170.31970.6935-0.2604-0.3254-0.14970.206-0.0298-0.04720.2631-0.00580.1142-24.842736.2425-6.9621
176.03263.7889-2.09612.8-2.29062.98490.2086-0.00770.40220.5807-0.20830.6336-0.218-0.107-0.00040.1753-0.0077-0.01890.24770.01670.1695-25.805336.7878-2.2109
186.07072.40562.16048.61583.20815.86870.0467-0.1363-0.29930.3495-0.0122-0.18790.04970.1243-0.03380.13420.01010.01220.14270.03460.1232-59.455739.160535.4713
192.83831.0387-0.16772.8853-0.23060.78820.0894-0.0155-0.00090.0996-0.08220.07730.046-0.084-0.00030.0850.0077-0.00850.1143-0.00170.0768-59.765548.889230.6378
200.857-2.3065-1.47836.173.96022.5279-0.03340.01-0.37460.0054-0.39390.6777-0.0062-0.20940.36220.1385-0.0017-0.00160.1435-0.01990.3426-56.960826.179226.71
218.3162.6377-4.06352.6311-1.73253.51670.19130.06570.3642-0.1584-0.082-0.0478-0.12780.2095-0.09360.1498-0.01860.05040.197-0.02940.2069-26.992318.643913.0616
225.71770.5837-0.58972.418-0.00012.7374-0.0363-0.08620.16350.0495-0.03340.1156-0.12860.08660.0730.1439-0.03020.01590.0783-0.01810.1889-39.734921.968823.4762
234.1579-0.8032-1.10332.6930.36212.8851-0.1815-0.2415-0.690.0303-0.1286-0.24360.24270.31650.27490.14140.01320.04070.19110.03290.2594-31.174415.214323.3973
242.44380.3224-0.30272.70110.05121.6715-0.0270.0739-0.0117-0.02180.0375-0.07280.00290.065-0.00630.0797-0.0052-0.01950.09860.00960.1009-44.897957.938321.7296
252.25970.7176-0.16054.19210.49632.0972-0.06710.1864-0.2769-0.26310.10530.320.1643-0.503-0.03220.1274-0.0312-0.02940.30420.0060.2628-35.167326.24797.3001
265.7944-0.8301-2.36323.01751.87643.62260.09760.0924-0.1415-0.33880.0304-0.69020.24840.3570.13270.38280.15760.13220.14680.04390.33411.3498-7.765-24.4656
273.27892.365-4.71842.3477-3.73117.72440.0536-0.17440.12770.8059-0.11720.3156-0.3543-0.2135-0.03170.25530.02310.10420.1712-0.06110.2975-58.444466.457134.1571
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 75 )
2X-RAY DIFFRACTION2chain 'A' and (resid 76 through 113 )
3X-RAY DIFFRACTION3chain 'A' and (resid 114 through 187 )
4X-RAY DIFFRACTION4chain 'A' and (resid 188 through 208 )
5X-RAY DIFFRACTION5chain 'B' and (resid 2 through 28 )
6X-RAY DIFFRACTION6chain 'B' and (resid 29 through 52 )
7X-RAY DIFFRACTION7chain 'B' and (resid 52A through 63 )
8X-RAY DIFFRACTION8chain 'B' and (resid 64 through 82 )
9X-RAY DIFFRACTION9chain 'B' and (resid 82A through 96 )
10X-RAY DIFFRACTION10chain 'B' and (resid 97 through 111 )
11X-RAY DIFFRACTION11chain 'B' and (resid 112 through 134 )
12X-RAY DIFFRACTION12chain 'B' and (resid 135 through 145 )
13X-RAY DIFFRACTION13chain 'B' and (resid 146 through 157 )
14X-RAY DIFFRACTION14chain 'B' and (resid 158 through 175 )
15X-RAY DIFFRACTION15chain 'B' and (resid 176 through 188 )
16X-RAY DIFFRACTION16chain 'B' and (resid 189 through 203 )
17X-RAY DIFFRACTION17chain 'B' and (resid 204 through 214 )
18X-RAY DIFFRACTION18chain 'C' and (resid 2 through 24 )
19X-RAY DIFFRACTION19chain 'C' and (resid 25 through 101 )
20X-RAY DIFFRACTION20chain 'C' and (resid 102 through 113 )
21X-RAY DIFFRACTION21chain 'C' and (resid 114 through 129 )
22X-RAY DIFFRACTION22chain 'C' and (resid 130 through 173 )
23X-RAY DIFFRACTION23chain 'C' and (resid 174 through 208 )
24X-RAY DIFFRACTION24chain 'D' and (resid 2 through 111 )
25X-RAY DIFFRACTION25chain 'D' and (resid 112 through 214 )
26X-RAY DIFFRACTION26chain 'G' and (resid 6 through 14 )
27X-RAY DIFFRACTION27chain 'I' and (resid 6 through 14 )

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