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- PDB-8eli: Broadly neutralizing antibody VRC34-combo.1 in complex with HIV f... -

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Basic information

Entry
Database: PDB / ID: 8eli
TitleBroadly neutralizing antibody VRC34-combo.1 in complex with HIV fusion peptide (residue 512-519)
Components
  • Fusion peptide
  • VRC34-combo.1 Fab Heavy chain
  • VRC34-combo.1 Fab Light chain
KeywordsIMMUNE SYSTEM / HIV / VRC34 / Fusion peptide / broadly neutralizing
Biological speciesHomo sapiens (human)
HIV-1 06TG.HT008 (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.49 Å
AuthorsXu, K. / Kwong, P.D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2023
Title: Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site.
Authors: Bailey B Banach / Sergei Pletnev / Adam S Olia / Kai Xu / Baoshan Zhang / Reda Rawi / Tatsiana Bylund / Nicole A Doria-Rose / Thuy Duong Nguyen / Ahmed S Fahad / Myungjin Lee / Bob C Lin / ...Authors: Bailey B Banach / Sergei Pletnev / Adam S Olia / Kai Xu / Baoshan Zhang / Reda Rawi / Tatsiana Bylund / Nicole A Doria-Rose / Thuy Duong Nguyen / Ahmed S Fahad / Myungjin Lee / Bob C Lin / Tracy Liu / Mark K Louder / Bharat Madan / Krisha McKee / Sijy O'Dell / Mallika Sastry / Arne Schön / Natalie Bui / Chen-Hsiang Shen / Jacy R Wolfe / Gwo-Yu Chuang / John R Mascola / Peter D Kwong / Brandon J DeKosky /
Abstract: The HIV-1 fusion peptide (FP) represents a promising vaccine target, but global FP sequence diversity among circulating strains has limited anti-FP antibodies to ~60% neutralization breadth. Here we ...The HIV-1 fusion peptide (FP) represents a promising vaccine target, but global FP sequence diversity among circulating strains has limited anti-FP antibodies to ~60% neutralization breadth. Here we evolve the FP-targeting antibody VRC34.01 in vitro to enhance FP-neutralization using site saturation mutagenesis and yeast display. Successive rounds of directed evolution by iterative selection of antibodies for binding to resistant HIV-1 strains establish a variant, VRC34.01_mm28, as a best-in-class antibody with 10-fold enhanced potency compared to the template antibody and ~80% breadth on a cross-clade 208-strain neutralization panel. Structural analyses demonstrate that the improved paratope expands the FP binding groove to accommodate diverse FP sequences of different lengths while also recognizing the HIV-1 Env backbone. These data reveal critical antibody features for enhanced neutralization breadth and potency against the FP site of vulnerability and accelerate clinical development of broad HIV-1 FP-targeting vaccines and therapeutics.
History
DepositionSep 24, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 14, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: VRC34-combo.1 Fab Light chain
H: VRC34-combo.1 Fab Heavy chain
A: Fusion peptide


Theoretical massNumber of molelcules
Total (without water)48,1643
Polymers48,1643
Non-polymers00
Water11,277626
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4630 Å2
ΔGint-33 kcal/mol
Surface area20090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.323, 86.152, 128.824
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 VRC34-combo.1 Fab Light chain


Mass: 23281.867 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 VRC34-combo.1 Fab Heavy chain


Mass: 24149.062 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 Fusion peptide


Mass: 732.868 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) HIV-1 06TG.HT008 (virus)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 626 / 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: 2.21 Å3/Da / Density % sol: 44.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 40% MPD, 0.1 mM sodium potassium phosphate pH6.2

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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: Apr 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.36→50 Å / Num. obs: 85913 / % possible obs: 92.4 % / Redundancy: 10.2 % / Biso Wilson estimate: 12.81 Å2 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.023 / Rrim(I) all: 0.074 / Χ2: 1.267 / Net I/σ(I): 8.4 / Num. measured all: 873310
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.36-1.386.30.54825460.8670.230.5960.36355.5
1.38-1.417.10.4928960.8980.1950.530.37663.2
1.41-1.447.50.45232580.9140.1760.4870.41371.2
1.44-1.478.40.40736940.9360.1470.4350.43480.2
1.47-1.59.50.34642000.9650.1170.3660.49791.9
1.5-1.5310.90.30746120.9790.0970.3220.598100
1.53-1.5711.10.27745870.9830.0860.290.712100
1.57-1.6111.20.23745970.9870.0740.2490.825100
1.61-1.6611.10.20846200.9910.0650.2180.92199.9
1.66-1.71110.19245620.990.060.2011.00199.3
1.71-1.7710.70.16145730.9940.0510.1691.15999
1.77-1.85100.13744930.9930.0450.1441.32897
1.85-1.9311.10.11746230.9960.0370.1231.53799.7
1.93-2.0310.80.146250.9970.0320.1051.74799.7
2.03-2.1610.90.08846150.9970.0280.0931.9599.2
2.16-2.3310.60.07746340.9970.0250.0812.0499.6
2.33-2.569.90.06846010.9970.0230.072297.7
2.56-2.9310.60.05846480.9980.0190.0611.94498.5
2.93-3.6910.50.04646550.9990.0150.0491.99397.8
3.69-50100.03548740.9990.0120.0371.53597.1

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I8C

5i8c


Resolution: 1.49→36.73 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 16.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.178 3450 4.93 %
Rwork0.162 66508 -
obs0.1628 69958 98.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 70.11 Å2 / Biso mean: 17.8941 Å2 / Biso min: 4.81 Å2
Refinement stepCycle: final / Resolution: 1.49→36.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3387 0 0 626 4013
Biso mean---30.67 -
Num. residues----447
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 25

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.49-1.510.2051230.18482508263194
1.51-1.530.231630.17962654281799
1.53-1.550.20811330.172926072740100
1.55-1.580.21951300.169426632793100
1.58-1.60.19921480.161326572805100
1.6-1.630.20421450.166326342779100
1.63-1.660.18451300.153926672797100
1.66-1.690.18081120.16822660277299
1.69-1.730.17761450.16572633277899
1.73-1.760.18481170.17032640275799
1.76-1.810.19491370.17962622275998
1.81-1.850.21041350.17882547268296
1.85-1.90.20281390.162226782817100
1.9-1.960.17861400.154826702810100
1.96-2.020.19671370.15426992836100
2.02-2.090.1781370.15852646278399
2.09-2.180.15621560.150626492805100
2.18-2.280.16151460.153127112857100
2.28-2.40.18181360.16782684282099
2.4-2.550.19011130.16942665277897
2.55-2.740.19041580.16962635279398
2.74-3.020.1541320.16932692282499
3.02-3.450.1711440.15572711285598
3.45-4.350.16951330.14432728286198
4.35-36.730.15891610.16822848300997

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