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- PDB-7sg6: Structure of PfCSP peptide 21 with antibody CIS43_Var10 -

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Basic information

Entry
Database: PDB / ID: 7sg6
TitleStructure of PfCSP peptide 21 with antibody CIS43_Var10
Components
  • CIS43_Var10 Fab Heavy chain
  • CIS43_Var10 Fab Light chain
  • PfCSP peptide 21
KeywordsIMMUNE SYSTEM / Antibody / Plasmodium falciparum
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 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
Revision 1.3Oct 30, 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
H: CIS43_Var10 Fab Heavy chain
L: CIS43_Var10 Fab Light chain
A: PfCSP peptide 21
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,0974
Polymers50,0053
Non-polymers921
Water5,459303
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5460 Å2
ΔGint-34 kcal/mol
Surface area19250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.790, 61.570, 74.984
Angle α, β, γ (deg.)90.000, 105.930, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Antibody CIS43_Var10 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_Var10 Fab Light chain


Mass: 24160.670 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Protein/peptide PfCSP peptide 21


Mass: 1562.553 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 303 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.08 Å3/Da / Density % sol: 40.91 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 15% ISOPROPANOL, 0.2M AMMONIUM CITRATE pH 3.5, 25% PEG 3,350

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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 29, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.55→44.96 Å / Num. obs: 58909 / % possible obs: 98.6 % / Redundancy: 3.5 % / CC1/2: 0.985 / Rmerge(I) obs: 0.132 / Net I/σ(I): 5.6
Reflection shellResolution: 1.55→1.6 Å / Rmerge(I) obs: 0.846 / Num. unique obs: 5896 / CC1/2: 0.56

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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: 1.55→44.96 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 21.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.211 2929 4.98 %
Rwork0.1843 55895 -
obs0.1857 58824 98.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 49.22 Å2 / Biso mean: 16.408 Å2 / Biso min: 5.77 Å2
Refinement stepCycle: final / Resolution: 1.55→44.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3447 0 14 303 3764
Biso mean--19.49 22.16 -
Num. residues----452
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.55-1.580.27691190.2419268199
1.58-1.60.2721090.233270399
1.6-1.630.27931430.2286262699
1.63-1.660.27161230.2277269599
1.66-1.70.25031240.2228268599
1.7-1.730.26281440.2064263799
1.73-1.770.25471380.2028261398
1.77-1.820.21461510.1996260697
1.82-1.870.24171760.1919258796
1.87-1.920.21711570.18261799
1.92-1.980.2161320.1775265499
1.98-2.060.20681440.1804267299
2.06-2.140.22721360.1735269199
2.14-2.240.18371310.1721269699
2.24-2.350.19611350.1822267899
2.35-2.50.21811380.1983262598
2.5-2.690.23321330.1946262297
2.69-2.960.22381410.1926270099
2.96-3.390.21711500.1811265899
3.39-4.280.181610.1587271999

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