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

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Basic information

Entry
Database: PDB / ID: 5ukq
TitleStructure of unliganded anti-gp120 CD4bs antibody DH522.2 Fab
Components
  • 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)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 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 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,3773
Polymers47,2852
Non-polymers921
Water4,738263
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3590 Å2
ΔGint-24 kcal/mol
Surface area19010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.074, 79.217, 184.745
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11H-374-

HOH

21H-404-

HOH

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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: 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
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 263 / Source method: isolated from a natural source / Formula: H2O

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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: 2.64 Å3/Da / Density % sol: 53.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.075 M Tris-HCl pH 8.5, 1.5 M ammonium sulfate, 25% glycerol

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jan 11, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 30338 / % possible obs: 96.3 % / Redundancy: 4 % / Rsym value: 0.122 / Net I/σ(I): 12.1

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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: 5UKP

5ukp


Resolution: 2.1→24.31 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 25.64
RfactorNum. reflection% reflection
Rfree0.2295 1794 6.61 %
Rwork0.1736 --
obs0.1773 27150 89.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.1→24.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3239 0 6 263 3508
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083325
X-RAY DIFFRACTIONf_angle_d1.1744530
X-RAY DIFFRACTIONf_dihedral_angle_d12.9711158
X-RAY DIFFRACTIONf_chiral_restr0.043518
X-RAY DIFFRACTIONf_plane_restr0.005575
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.15670.2771250.21531772X-RAY DIFFRACTION83
2.1567-2.22020.31981270.2571658X-RAY DIFFRACTION77
2.2202-2.29180.33071100.25331555X-RAY DIFFRACTION72
2.2918-2.37360.30121230.20411855X-RAY DIFFRACTION86
2.3736-2.46860.26731400.21351913X-RAY DIFFRACTION89
2.4686-2.58080.2911360.21311969X-RAY DIFFRACTION91
2.5808-2.71670.27311370.20841969X-RAY DIFFRACTION90
2.7167-2.88670.27431450.19112012X-RAY DIFFRACTION93
2.8867-3.10910.25831460.18852074X-RAY DIFFRACTION94
3.1091-3.42120.24431460.17332104X-RAY DIFFRACTION96
3.4212-3.91450.20521430.1561996X-RAY DIFFRACTION91
3.9145-4.92510.16671540.12462186X-RAY DIFFRACTION98
4.9251-24.31110.19461620.16282293X-RAY DIFFRACTION99
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)
11.2434-0.083-0.46141.03240.44793.69390.0360.2474-0.1073-0.2105-0.05020.0824-0.1113-0.26990.01860.279-0.0102-0.03220.27860.0080.2433-4.0673-0.1031-27.9985
23.46790.7624-3.22051.3966-0.78673.01310.33690.00420.2223-0.0094-0.00430.1044-0.47890.3806-0.19090.3351-0.068-0.03610.2982-0.00820.2788-1.27684.4741-16.7939
30.754-1.2629-0.28242.19790.04643.2687-0.0632-0.15550.63-0.0881-0.10560.1812-0.16790.51340.04170.2461-0.0274-0.00040.30280.02840.30052.76718.65021.1499
44.09342.2920.07933.7811-0.29221.635-0.0920.10380.5558-0.0731-0.01140.1737-0.10650.09050.11470.2584-0.0035-0.01440.25510.01110.36065.520821.7858-4.8158
50.56570.21931.19774.37320.9624.8152-0.02810.255-0.2504-0.19450.0894-0.2880.19680.4501-0.18040.20960.0468-0.00470.4213-0.05870.240920.9236-5.4104-24.1548
61.67540.89970.53282.49930.40152.499-0.08010.2782-0.0239-0.30440.1386-0.1019-0.11740.3348-0.0460.321-0.01940.0170.3952-0.01220.267615.2284-1.9305-33.7979
73.41960.79130.69411.52530.25472.51340.0214-0.05440.046-0.129-0.0355-0.046-0.10060.24360.03180.2499-0.00340.0190.3096-0.03110.228516.4831-0.9508-26.9236
82.3039-0.1014-0.00361.69280.1342.76350.03040.04770.0787-0.0707-0.0815-0.0839-0.0197-0.03420.06750.2145-0.0012-0.00440.2476-0.01850.253417.366613.75573.8226
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain H and resid 2:102)
2X-RAY DIFFRACTION2(chain H and resid 103:113)
3X-RAY DIFFRACTION3(chain H and resid 114:133)
4X-RAY DIFFRACTION4(chain H and resid 134:215)
5X-RAY DIFFRACTION5(chain L and resid 1:17)
6X-RAY DIFFRACTION6(chain L and resid 18:72)
7X-RAY DIFFRACTION7(chain L and resid 73:108)
8X-RAY DIFFRACTION8(chain L and resid 109:209)

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