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- PDB-6peh: Crystal structure of rabbit monoclonal anti-HIV antibody 1C2 -

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Basic information

Entry
Database: PDB / ID: 6peh
TitleCrystal structure of rabbit monoclonal anti-HIV antibody 1C2
Components
  • 1C2 Fab Heavy Chain
  • 1C2 Fab Light Chain
KeywordsIMMUNE SYSTEM / Antibody / bnAb / HIV
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.296 Å
AuthorsLiban, T. / Pancera, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)P01AI104722 United States
CitationJournal: Immunity / Year: 2019
Title: Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability.
Authors: Viktoriya Dubrovskaya / Karen Tran / Gabriel Ozorowski / Javier Guenaga / Richard Wilson / Shridhar Bale / Christopher A Cottrell / Hannah L Turner / Gemma Seabright / Sijy O'Dell / Jonathan ...Authors: Viktoriya Dubrovskaya / Karen Tran / Gabriel Ozorowski / Javier Guenaga / Richard Wilson / Shridhar Bale / Christopher A Cottrell / Hannah L Turner / Gemma Seabright / Sijy O'Dell / Jonathan L Torres / Lifei Yang / Yu Feng / Daniel P Leaman / Néstor Vázquez Bernat / Tyler Liban / Mark Louder / Krisha McKee / Robert T Bailer / Arlette Movsesyan / Nicole A Doria-Rose / Marie Pancera / Gunilla B Karlsson Hedestam / Michael B Zwick / Max Crispin / John R Mascola / Andrew B Ward / Richard T Wyatt /
Abstract: The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are ...The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.
History
DepositionJun 20, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 20, 2019Provider: repository / Type: Initial release
Revision 2.0Nov 27, 2019Group: Database references / Polymer sequence / Category: citation / citation_author / entity_poly
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _entity_poly.pdbx_seq_one_letter_code_can
Revision 2.1Dec 4, 2019Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 2.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support
Item: _pdbx_audit_support.country / _pdbx_audit_support.funding_organization

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: 1C2 Fab Heavy Chain
L: 1C2 Fab Light Chain
A: 1C2 Fab Heavy Chain
B: 1C2 Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,8876
Polymers95,6954
Non-polymers1922
Water4,828268
1
H: 1C2 Fab Heavy Chain
L: 1C2 Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,9433
Polymers47,8472
Non-polymers961
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3830 Å2
ΔGint-40 kcal/mol
Surface area19230 Å2
MethodPISA
2
A: 1C2 Fab Heavy Chain
B: 1C2 Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,9433
Polymers47,8472
Non-polymers961
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3820 Å2
ΔGint-44 kcal/mol
Surface area19260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.799, 98.610, 162.983
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

#1: Antibody 1C2 Fab Heavy Chain


Mass: 25017.061 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody 1C2 Fab Light Chain


Mass: 22830.307 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / Source method: isolated from a natural source / Formula: H2O
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: 3.01 Å3/Da / Density % sol: 59.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M Imidazole pH 6.5, 16% PEG 3350, 10% MPD, 0.2M LiSO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Mar 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.296→50 Å / Num. obs: 46339 / % possible obs: 88 % / Redundancy: 3.7 % / Net I/σ(I): 12.4
Reflection shellResolution: 2.296→2.34 Å / Num. unique obs: 2060

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.296→43.323 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.14
RfactorNum. reflection% reflection
Rfree0.2546 2127 4.95 %
Rwork0.2193 --
obs0.221 42973 81.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.296→43.323 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6413 0 10 268 6691
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0046659
X-RAY DIFFRACTIONf_angle_d0.7179148
X-RAY DIFFRACTIONf_dihedral_angle_d13.9833924
X-RAY DIFFRACTIONf_chiral_restr0.0461078
X-RAY DIFFRACTIONf_plane_restr0.0041159
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2962-2.34960.4333740.30511445X-RAY DIFFRACTION44
2.3496-2.40840.26531280.27732107X-RAY DIFFRACTION65
2.4084-2.47350.28731240.27352560X-RAY DIFFRACTION77
2.4735-2.54630.30081480.26932829X-RAY DIFFRACTION86
2.5463-2.62850.34481620.28142910X-RAY DIFFRACTION90
2.6285-2.72240.30751420.2713021X-RAY DIFFRACTION91
2.7224-2.83140.2881620.25562946X-RAY DIFFRACTION90
2.8314-2.96020.32831650.25242892X-RAY DIFFRACTION88
2.9602-3.11620.28111540.24163030X-RAY DIFFRACTION92
3.1162-3.31140.24961630.23563026X-RAY DIFFRACTION91
3.3114-3.5670.24951290.20832990X-RAY DIFFRACTION89
3.567-3.92570.27911360.20262875X-RAY DIFFRACTION86
3.9257-4.49330.21671440.17432639X-RAY DIFFRACTION78
4.4933-5.6590.17041350.15842773X-RAY DIFFRACTION82
5.659-43.33090.20411610.19932803X-RAY DIFFRACTION79
Refinement TLS params.Method: refined / Origin x: -21.6525 Å / Origin y: -7.0405 Å / Origin z: 36.1152 Å
111213212223313233
T0.1107 Å20.0198 Å20.1651 Å2-0.0213 Å20.0973 Å2--0.0198 Å2
L0.5083 °20.0737 °2-0.2692 °2--0.1327 °20.8128 °2--0.2732 °2
S0.0428 Å °-0.0328 Å °0.0091 Å °-0.0002 Å °0.137 Å °0.1291 Å °0.2205 Å °0.2477 Å °0.1465 Å °
Refinement TLS groupSelection details: all

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