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- PDB-5ukr: Structure of unliganded anti-gp120 CD4bs antibody DH522.2 Fab in ... -

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Basic information

Entry
Database: PDB / ID: 5ukr
TitleStructure of unliganded anti-gp120 CD4bs antibody DH522.2 Fab in complex with a gp120 core
Components
  • Chimeric B.YU2 gp120 core derived from HIV-1 Env
  • DH522.2 Fab fragment heavy chain
  • DH522.2 Fab fragment light chain
KeywordsIMMUNE SYSTEM / HIV gp120 immune system
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesMacaca mulatta (Rhesus monkey)
Human immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.712 Å
AuthorsNicely, N.I.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)UM1-AI100645 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01-AI087202 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01-AI118571 United States
Duke University Center for AIDS ResearchP30-AI-64518 United States
CitationJournal: Nat Commun / Year: 2017
Title: Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.
Authors: Wilton B Williams / Jinsong Zhang / Chuancang Jiang / Nathan I Nicely / Daniela Fera / Kan Luo / M Anthony Moody / Hua-Xin Liao / S Munir Alam / Thomas B Kepler / Akshaya Ramesh / Kevin ...Authors: Wilton B Williams / Jinsong Zhang / Chuancang Jiang / Nathan I Nicely / Daniela Fera / Kan Luo / M Anthony Moody / Hua-Xin Liao / S Munir Alam / Thomas B Kepler / Akshaya Ramesh / Kevin Wiehe / James A Holland / Todd Bradley / Nathan Vandergrift / Kevin O Saunders / Robert Parks / Andrew Foulger / Shi-Mao Xia / Mattia Bonsignori / David C Montefiori / Mark Louder / Amanda Eaton / Sampa Santra / Richard Scearce / Laura Sutherland / Amanda Newman / Hilary Bouton-Verville / Cindy Bowman / Howard Bomze / Feng Gao / Dawn J Marshall / John F Whitesides / Xiaoyan Nie / Garnett Kelsoe / Steven G Reed / Christopher B Fox / Kim Clary / Marguerite Koutsoukos / David Franco / John R Mascola / Stephen C Harrison / Barton F Haynes / Laurent Verkoczy /
Abstract: A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report ...A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice EnvB cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools.
History
DepositionJan 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Oct 23, 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
H: DH522.2 Fab fragment heavy chain
L: DH522.2 Fab fragment light chain
G: Chimeric B.YU2 gp120 core derived from HIV-1 Env
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,4519
Polymers82,1243
Non-polymers1,3276
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6950 Å2
ΔGint-11 kcal/mol
Surface area29930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.851, 71.973, 252.228
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Antibody DH522.2 Fab fragment heavy chain


Mass: 24412.223 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca mulatta (Rhesus monkey) / Cell line (production host): HEK 293F / Production host: Homo sapiens (human)
#2: Antibody DH522.2 Fab fragment light chain


Mass: 22873.121 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca mulatta (Rhesus monkey) / Cell line (production host): HEK 293F / Production host: Homo sapiens (human)
#3: Protein Chimeric B.YU2 gp120 core derived from HIV-1 Env


Mass: 34838.691 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Cell line (production host): HEK 293S GnTI-/- / Production host: Homo sapiens (human)
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 2.88 Å3/Da / Density % sol: 57.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M MES pH 6.5, 12% PEG 20,000

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 25631 / % possible obs: 98.6 % / Redundancy: 4.8 % / Rsym value: 0.14 / Net I/σ(I): 13.5

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: The starting model for the Fab component was 5UKP. The starting model for the gp120 component was PDB 4R4H.

5ukp

4r4h


Resolution: 2.712→49.848 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 27.38
RfactorNum. reflection% reflection
Rfree0.2647 2000 7.82 %
Rwork0.2011 --
obs0.2061 25574 98.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.712→49.848 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4937 0 0 17 4954
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0085048
X-RAY DIFFRACTIONf_angle_d1.2676856
X-RAY DIFFRACTIONf_dihedral_angle_d14.9061778
X-RAY DIFFRACTIONf_chiral_restr0.052801
X-RAY DIFFRACTIONf_plane_restr0.005868
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7122-2.780.33851340.25841576X-RAY DIFFRACTION93
2.78-2.85510.32751420.25141667X-RAY DIFFRACTION100
2.8551-2.93920.34971410.24351674X-RAY DIFFRACTION100
2.9392-3.0340.3051430.25221692X-RAY DIFFRACTION100
3.034-3.14240.34451450.24431697X-RAY DIFFRACTION100
3.1424-3.26820.34231430.2231693X-RAY DIFFRACTION100
3.2682-3.41690.28041430.20951686X-RAY DIFFRACTION100
3.4169-3.5970.24211440.19641691X-RAY DIFFRACTION100
3.597-3.82230.21911450.19321703X-RAY DIFFRACTION100
3.8223-4.11730.25281420.18011677X-RAY DIFFRACTION99
4.1173-4.53140.2261420.15551681X-RAY DIFFRACTION97
4.5314-5.18650.1971440.15021692X-RAY DIFFRACTION97
5.1865-6.53220.25181430.19581696X-RAY DIFFRACTION96
6.5322-49.85640.28331490.23011749X-RAY DIFFRACTION94
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)
11.7233-0.60320.270.7751-0.69861.82220.27540.5698-0.2684-0.5824-0.13170.0138-0.00920.0733-0.15171.0058-0.06520.12230.8006-0.00090.39374.679985.01879.6151
22.09980.0664-0.06631.60050.81672.1819-0.03580.546-0.1107-0.6905-0.05190.1165-0.4493-0.35180.07970.9381-0.0407-0.11910.6583-0.01260.3369-12.542288.957919.2473
31.0955-0.11110.24043.2173-1.15663.07550.1191-0.066-0.1059-0.429-0.0230.0388-0.0118-0.0694-0.070.1712-0.03920.02770.1937-0.01770.2211-3.146586.296348.4767
42.44450.3709-0.13464.5312-0.61752.05170.0406-0.29170.3470.3231-0.03690.1063-0.4187-0.19120.00020.24480.04940.01320.2598-0.0060.329810.306488.180576.5686
53.0893-0.36060.17521.1275-0.32160.78040.08640.11160.0187-0.55290.2341-0.4771-0.62970.4427-0.18630.442-0.22650.24940.4261-0.14580.404816.026787.693439.746
62.00960.6125-1.16752.63240.85882.9789-0.1795-0.1652-0.14740.33850.0268-0.80780.33140.28690.15540.23490.0947-0.02550.29580.00890.553624.203479.262976.4528
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain G and resid 90:253)
2X-RAY DIFFRACTION2(chain G and resid 254:388)
3X-RAY DIFFRACTION3(chain H and resid 1:115)
4X-RAY DIFFRACTION4(chain H and resid 116:215)
5X-RAY DIFFRACTION5(chain L and resid 3:107)
6X-RAY DIFFRACTION6(chain L and resid 108:208)

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