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- PDB-8ekf: X-ray crystal structure of 311R Fab in complex with the PfCSP pep... -

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Basic information

Entry
Database: PDB / ID: 8ekf
TitleX-ray crystal structure of 311R Fab in complex with the PfCSP peptide NPNA-3
Components
  • 311R Heavy Chain
  • 311R Light Chain
  • PfCSP peptide NPNA-3
KeywordsIMMUNE SYSTEM / Antibody / Antigen / Malaria
Biological speciesHomo sapiens (human)
Plasmodium falciparum 3D7 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsMoskovitz, R. / Wilson, I.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationINV-004923 United States
CitationJournal: Nat Commun / Year: 2023
Title: Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection.
Authors: Gregory M Martin / Jonathan L Torres / Tossapol Pholcharee / David Oyen / Yevel Flores-Garcia / Grace Gibson / Re'em Moskovitz / Nathan Beutler / Diana D Jung / Jeffrey Copps / Wen-Hsin Lee ...Authors: Gregory M Martin / Jonathan L Torres / Tossapol Pholcharee / David Oyen / Yevel Flores-Garcia / Grace Gibson / Re'em Moskovitz / Nathan Beutler / Diana D Jung / Jeffrey Copps / Wen-Hsin Lee / Gonzalo Gonzalez-Paez / Daniel Emerling / Randall S MacGill / Emily Locke / C Richter King / Fidel Zavala / Ian A Wilson / Andrew B Ward /
Abstract: The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an ...The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family.
History
DepositionSep 20, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 19, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 1, 2023Group: 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 1.3Oct 30, 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
HHH: 311R Heavy Chain
LLL: 311R Light Chain
CCC: PfCSP peptide NPNA-3


Theoretical massNumber of molelcules
Total (without water)47,9743
Polymers47,9743
Non-polymers00
Water3,135174
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4530 Å2
ΔGint-32 kcal/mol
Surface area19840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.412, 70.765, 170.246
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Antibody 311R Heavy Chain


Mass: 23927.830 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 311R Light Chain


Mass: 22839.268 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 NPNA-3


Mass: 1207.210 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Plasmodium falciparum 3D7 (eukaryote)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 174 / 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: 2.85 Å3/Da / Density % sol: 56.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 0.04 M KH2PO4, 20% Glycerol, and 16% PEG3000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-1 / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 24, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.9→44.27 Å / Num. obs: 44216 / % possible obs: 99.8 % / Redundancy: 3.3 % / CC1/2: 0.99 / Rmerge(I) obs: 0.055 / Net I/σ(I): 17.2
Reflection shellResolution: 1.9→1.94 Å / Redundancy: 2.3 % / Num. unique obs: 4800 / CC1/2: 0.96 / % possible all: 97.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
Cootmodel building
PHASERphasing
Aimlessdata reduction
pointlessdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6AXK

6axk


Resolution: 1.9→44.27 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.95 / SU B: 3.092 / SU ML: 0.087 / Cross valid method: FREE R-VALUE / ESU R: 0.126 / ESU R Free: 0.124
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2216 2192 4.971 %
Rwork0.1839 41903 -
all0.186 --
obs-44095 99.726 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 37.602 Å2
Baniso -1Baniso -2Baniso -3
1-1.15 Å20 Å20 Å2
2---0.472 Å20 Å2
3----0.678 Å2
Refinement stepCycle: LAST / Resolution: 1.9→44.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3323 0 0 174 3497
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0133412
X-RAY DIFFRACTIONr_bond_other_d0.0010.0153104
X-RAY DIFFRACTIONr_angle_refined_deg1.7181.6434660
X-RAY DIFFRACTIONr_angle_other_deg1.4081.5747191
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5865444
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.62423.06134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.81715506
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.3821511
X-RAY DIFFRACTIONr_chiral_restr0.0780.2449
X-RAY DIFFRACTIONr_gen_planes_refined0.010.023904
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02754
X-RAY DIFFRACTIONr_nbd_refined0.1930.2526
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1880.22750
X-RAY DIFFRACTIONr_nbtor_refined0.1690.21633
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0840.21695
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1540.2156
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1880.211
X-RAY DIFFRACTIONr_nbd_other0.1730.239
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1530.210
X-RAY DIFFRACTIONr_mcbond_it3.5843.7931785
X-RAY DIFFRACTIONr_mcbond_other3.5693.7911784
X-RAY DIFFRACTIONr_mcangle_it4.8185.6612226
X-RAY DIFFRACTIONr_mcangle_other4.8215.6622227
X-RAY DIFFRACTIONr_scbond_it4.2764.0811627
X-RAY DIFFRACTIONr_scbond_other4.2754.0821628
X-RAY DIFFRACTIONr_scangle_it6.2135.9332434
X-RAY DIFFRACTIONr_scangle_other6.2125.9352435
X-RAY DIFFRACTIONr_lrange_it7.8644.0693585
X-RAY DIFFRACTIONr_lrange_other7.82843.923561
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.9490.3061440.2932979X-RAY DIFFRACTION97.8077
1.949-2.0030.2611580.2472984X-RAY DIFFRACTION99.9364
2.003-2.0610.2611660.2282902X-RAY DIFFRACTION99.8698
2.061-2.1240.2381610.2012778X-RAY DIFFRACTION99.898
2.124-2.1940.2361440.1932734X-RAY DIFFRACTION99.8959
2.194-2.2710.2291380.1912680X-RAY DIFFRACTION99.9291
2.271-2.3560.2961180.1922543X-RAY DIFFRACTION99.8125
2.356-2.4520.2231200.1932482X-RAY DIFFRACTION99.8082
2.452-2.5610.2361240.1882378X-RAY DIFFRACTION99.8802
2.561-2.6860.2181270.1722257X-RAY DIFFRACTION99.8743
2.686-2.8310.2291170.1752174X-RAY DIFFRACTION100
2.831-3.0030.2011050.1712052X-RAY DIFFRACTION99.9537
3.003-3.210.2471140.1821930X-RAY DIFFRACTION99.9511
3.21-3.4670.204880.1681804X-RAY DIFFRACTION99.5789
3.467-3.7970.174870.1741682X-RAY DIFFRACTION99.8307
3.797-4.2440.225900.1741508X-RAY DIFFRACTION99.9375
4.244-4.8990.212680.1651363X-RAY DIFFRACTION99.9302
4.899-5.9950.237500.1891179X-RAY DIFFRACTION99.9187
5.995-8.4570.169390.189937X-RAY DIFFRACTION99.7955

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