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- PDB-7sg5: Structure of PfCSP peptide 21 with antibody CIS43_Var2 -

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Basic information

Entry
Database: PDB / ID: 7sg5
TitleStructure of PfCSP peptide 21 with antibody CIS43_Var2
Components
  • (CIS43_Var2 Fab ...) x 2
  • PfCSP peptide 21
KeywordsIMMUNE SYSTEM / Antibody / Plasmodium falciparum
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsTripathi, P. / Kwong, P.D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: J Exp Med / Year: 2022
Title: Highly protective antimalarial antibodies via precision library generation and yeast display screening.
Authors: Bailey B Banach / Prabhanshu Tripathi / Lais Da Silva Pereira / Jason Gorman / Thuy Duong Nguyen / Marlon Dillon / Ahmed S Fahad / Patience K Kiyuka / Bharat Madan / Jacy R Wolfe / Brian ...Authors: Bailey B Banach / Prabhanshu Tripathi / Lais Da Silva Pereira / Jason Gorman / Thuy Duong Nguyen / Marlon Dillon / Ahmed S Fahad / Patience K Kiyuka / Bharat Madan / Jacy R Wolfe / Brian Bonilla / Barbara Flynn / Joseph R Francica / Nicholas K Hurlburt / Neville K Kisalu / Tracy Liu / Li Ou / Reda Rawi / Arne Schön / Chen-Hsiang Shen / I-Ting Teng / Baoshan Zhang / Marie Pancera / Azza H Idris / Robert A Seder / Peter D Kwong / Brandon J DeKosky /
Abstract: The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. ...The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturation mutagenesis and DNA shuffling to screen precise gene-variant yeast display libraries for improved PfCSP antigen recognition. We identified several mutations that improved recognition, predominately in framework regions, and combined these to produce a panel of antibody variants. The most improved antibody, CIS43_Var10, had three mutations and showed approximately sixfold enhanced protective potency in vivo compared to CIS43. Co-crystal and cryo-electron microscopy structures of CIS43_Var10 with the peptide epitope or with PfCSP, respectively, revealed functional roles for each of these mutations. The unbiased site-directed mutagenesis and screening pipeline described here represent a powerful approach to enhance protective potency and to enable broader clinical use of antimalarial antibodies.
History
DepositionOct 5, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 22, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 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

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Assembly

Deposited unit
H: CIS43_Var2 Fab Heavy chain
L: CIS43_Var2 Fab Light chain
A: PfCSP peptide 21
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,5899
Polymers50,0173
Non-polymers5726
Water6,702372
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6280 Å2
ΔGint-85 kcal/mol
Surface area19240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.770, 61.137, 75.313
Angle α, β, γ (deg.)90.000, 106.560, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein/peptide , 1 types, 1 molecules A

#3: Protein/peptide PfCSP peptide 21


Mass: 1562.553 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Antibody , 2 types, 2 molecules HL

#1: Antibody CIS43_Var2 Fab Heavy chain


Mass: 24281.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody CIS43_Var2 Fab Light chain


Mass: 24172.723 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Non-polymers , 3 types, 378 molecules

#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#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.: 372 / 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: 2.09 Å3/Da / Density % sol: 41.17 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 0.2 M ammonium sulfate, 28% w/v polyethylene glycol 4,000

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Data collection

DiffractionMean temperature: 298 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 19, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.4→50.72 Å / Num. obs: 61516 / % possible obs: 75.52 % / Redundancy: 2.1 % / CC1/2: 0.996 / Rmerge(I) obs: 0.044 / Net I/σ(I): 14.71
Reflection shellResolution: 1.4→1.45 Å / Rmerge(I) obs: 0.349 / Num. unique obs: 4587 / CC1/2: 0.82

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6B5M

6b5m


Resolution: 1.4→50.72 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2176 3047 4.97 %
Rwork0.1851 58277 -
obs0.1867 61324 75.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 48.08 Å2 / Biso mean: 19.3857 Å2 / Biso min: 9.18 Å2
Refinement stepCycle: final / Resolution: 1.4→50.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3443 0 31 372 3846
Biso mean--28.36 25.08 -
Num. residues----451
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.4-1.420.317980.2918187954
1.42-1.450.30941110.2701201258
1.45-1.470.31041220.2501226465
1.47-1.50.29251300.2279248071
1.5-1.530.24451460.2189269677
1.53-1.560.24261440.2144279380
1.56-1.590.28271460.206279581
1.59-1.630.22591350.1971280780
1.63-1.670.22321380.207282080
1.67-1.710.24991350.2045285781
1.71-1.760.25781370.1987279280
1.76-1.820.25731330.1966278079
1.82-1.890.21891280.1956279280
1.89-1.960.22691530.1893281281
1.96-2.050.22171690.1838276980
2.05-2.160.22281560.1806279680
2.16-2.290.24321470.1799276679
2.29-2.470.22721440.186274778
2.47-2.720.23731590.1889263875
2.72-3.110.21231300.1864271177
3.11-3.920.18471540.1674265575

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