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- PDB-6mqs: Vaccine-elicited NHP FP-targeting HIV neutralizing antibody A12V1... -

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Basic information

Entry
Database: PDB / ID: 6mqs
TitleVaccine-elicited NHP FP-targeting HIV neutralizing antibody A12V163-a.01 in complex with HIV fusion peptide (residue 512-519)
Components
  • HIV fusion peptide residue 512-519
  • antibody A12V163-a.01 heavy chain
  • antibody A12V163-a.01 light chain
KeywordsIMMUNE SYSTEM / HIV / neutralizing / NHP / FP / Fusion Peptide / vaccine
Function / homology
Function and homology information


Synthesis and processing of ENV and VPU / evasion of host immune response / Alpha-defensins / Dectin-2 family / Binding and entry of HIV virion / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / virus-mediated perturbation of host defense response / host cell endosome membrane ...Synthesis and processing of ENV and VPU / evasion of host immune response / Alpha-defensins / Dectin-2 family / Binding and entry of HIV virion / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / virus-mediated perturbation of host defense response / host cell endosome membrane / actin filament organization / Assembly Of The HIV Virion / Budding and maturation of HIV virion / clathrin-dependent endocytosis of virus by host cell / viral protein processing / symbiont entry into host cell / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / membrane
Similarity search - Function
Envelope glycoprotein Gp160 / Retroviral envelope protein / Retroviral envelope protein GP41-like / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Envelope glycoprotein gp160
Similarity search - Component
Biological speciesMacaca mulatta (Rhesus monkey)
Human immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.997 Å
AuthorsXu, K. / Wang, Y. / Kwong, P.D.
CitationJournal: Cell / Year: 2019
Title: Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.
Authors: Rui Kong / Hongying Duan / Zizhang Sheng / Kai Xu / Priyamvada Acharya / Xuejun Chen / Cheng Cheng / Adam S Dingens / Jason Gorman / Mallika Sastry / Chen-Hsiang Shen / Baoshan Zhang / ...Authors: Rui Kong / Hongying Duan / Zizhang Sheng / Kai Xu / Priyamvada Acharya / Xuejun Chen / Cheng Cheng / Adam S Dingens / Jason Gorman / Mallika Sastry / Chen-Hsiang Shen / Baoshan Zhang / Tongqing Zhou / Gwo-Yu Chuang / Cara W Chao / Ying Gu / Alexander J Jafari / Mark K Louder / Sijy O'Dell / Ariana P Rowshan / Elise G Viox / Yiran Wang / Chang W Choi / Martin M Corcoran / Angela R Corrigan / Venkata P Dandey / Edward T Eng / Hui Geng / Kathryn E Foulds / Yicheng Guo / Young D Kwon / Bob Lin / Kevin Liu / Rosemarie D Mason / Martha C Nason / Tiffany Y Ohr / Li Ou / Reda Rawi / Edward K Sarfo / Arne Schön / John P Todd / Shuishu Wang / Hui Wei / Winston Wu / / James C Mullikin / Robert T Bailer / Nicole A Doria-Rose / Gunilla B Karlsson Hedestam / Diana G Scorpio / Julie Overbaugh / Jesse D Bloom / Bridget Carragher / Clinton S Potter / Lawrence Shapiro / Peter D Kwong / John R Mascola /
Abstract: The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be ...The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.
History
DepositionOct 10, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2019Group: Data collection / 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.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 13, 2019Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: antibody A12V163-a.01 heavy chain
B: antibody A12V163-a.01 light chain
C: antibody A12V163-a.01 heavy chain
D: antibody A12V163-a.01 light chain
E: HIV fusion peptide residue 512-519
F: HIV fusion peptide residue 512-519


Theoretical massNumber of molelcules
Total (without water)95,0806
Polymers95,0806
Non-polymers00
Water0
1
A: antibody A12V163-a.01 heavy chain
B: antibody A12V163-a.01 light chain
E: HIV fusion peptide residue 512-519


Theoretical massNumber of molelcules
Total (without water)47,5403
Polymers47,5403
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4590 Å2
ΔGint-31 kcal/mol
Surface area19650 Å2
MethodPISA
2
C: antibody A12V163-a.01 heavy chain
D: antibody A12V163-a.01 light chain
F: HIV fusion peptide residue 512-519


Theoretical massNumber of molelcules
Total (without water)47,5403
Polymers47,5403
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4640 Å2
ΔGint-25 kcal/mol
Surface area19380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.781, 98.781, 261.009
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and resid 2 through 222)
21chain C
12chain B
22chain D
13chain E
23chain F

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and resid 2 through 222)A2 - 222
211chain CC2 - 222
112chain BB1 - 215
212chain DD1 - 215
113chain EE512 - 518
213chain FF512 - 518

NCS ensembles :
ID
1
2
3

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Components

#1: Antibody antibody A12V163-a.01 heavy chain


Mass: 23872.639 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca mulatta (Rhesus monkey) / Production host: Homo sapiens (human)
#2: Antibody antibody A12V163-a.01 light chain


Mass: 22934.254 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca mulatta (Rhesus monkey) / Production host: Homo sapiens (human)
#3: Protein/peptide HIV fusion peptide residue 512-519


Mass: 732.868 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Human immunodeficiency virus 1 / References: UniProt: P04578*PLUS

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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: 3.37 Å3/Da / Density % sol: 63.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.17 M NH4CH3CO2, 0.085 M acetate pH 4.6, 25.5% w/v PEG 4000, and 15% glycerol

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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 EIGER X 16M / Detector: PIXEL / Date: Feb 19, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 26605 / % possible obs: 98.9 % / Redundancy: 12.3 % / Biso Wilson estimate: 87.41 Å2 / Rmerge(I) obs: 0.106 / Rpim(I) all: 0.03 / Rrim(I) all: 0.11 / Χ2: 1.066 / Net I/σ(I): 6.4 / Num. measured all: 327292
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3-3.0510.90.8412100.9310.2440.8770.56394
3.05-3.1111.30.68812690.970.1970.7170.55394.8
3.11-3.1711.70.61912770.9710.1770.6450.59498.3
3.17-3.2312.30.52212970.9850.1480.5440.59498.8
3.23-3.312.40.45813060.9860.130.4770.61499.1
3.3-3.3812.80.35613120.9920.1010.3710.643100
3.38-3.4612.70.31513000.9950.0890.3270.65399.4
3.46-3.5612.60.2713280.9950.0760.2810.69299.6
3.56-3.6612.60.20613310.9970.0590.2150.76899.8
3.66-3.7812.60.18913130.9970.0540.1970.77999.2
3.78-3.9112.60.16713100.9960.0470.1730.89599.4
3.91-4.0712.50.14613280.9970.0410.1521.0499.6
4.07-4.2612.30.12313290.9970.0350.1281.22499
4.26-4.4812.20.10113220.9980.030.1061.48398.6
4.48-4.7612.10.08613370.9980.0240.0891.58299
4.76-5.1312.10.07613450.9990.0220.081.49699.6
5.13-5.6412.40.07513640.9990.0210.0781.4799.5
5.64-6.4612.60.07413820.9990.0210.0771.47999.8
6.46-8.1313.10.06141210.0170.0621.67299.9
8.13-5012.10.05315330.9990.0160.0552.08699.7

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.13_2998refinement
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.997→47.682 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 29.76
RfactorNum. reflection% reflection
Rfree0.2468 1360 5.16 %
Rwork0.2333 --
obs0.234 26350 98.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 153.26 Å2 / Biso mean: 96.5166 Å2 / Biso min: 59.84 Å2
Refinement stepCycle: final / Resolution: 2.997→47.682 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6620 0 0 0 6620
Num. residues----889
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1897X-RAY DIFFRACTION12.681TORSIONAL
12C1897X-RAY DIFFRACTION12.681TORSIONAL
21B1906X-RAY DIFFRACTION12.681TORSIONAL
22D1906X-RAY DIFFRACTION12.681TORSIONAL
31E44X-RAY DIFFRACTION12.681TORSIONAL
32F44X-RAY DIFFRACTION12.681TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.9974-3.10450.35821210.33092328244994
3.1045-3.22880.3391310.30552421255298
3.2288-3.37570.30661290.27982467259699
3.3757-3.55360.30731340.26392462259699
3.5536-3.77610.32621450.25232474261999
3.7761-4.06760.26961350.22982485262099
4.0676-4.47660.22071300.21132497262798
4.4766-5.12370.21561480.1952515266399
5.1237-6.45290.22771420.23882591273399
6.4529-47.68840.20621450.22142750289599

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