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- PDB-8f7z: VRC34.01_mm28 bound to fusion peptide -

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Basic information

Entry
Database: PDB / ID: 8f7z
TitleVRC34.01_mm28 bound to fusion peptide
Components
  • HIV-1 Env Fusion Peptide
  • VRC34_m228 Light Chain
  • VRC34_mm28 Heavy Chain
KeywordsVIRAL PROTEIN / FP-NEUTRALIZING ANTIBODY / FUSION PEPTIDE / HIV-1 / GLYCOPROTEIN / FP-TARGETING VACCINES
Biological speciesHomo sapiens (human)
Human immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsOlia, A.S. / Kwong, P.D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
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
DepositionNov 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 1, 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

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Assembly

Deposited unit
I: HIV-1 Env Fusion Peptide
E: VRC34_mm28 Heavy Chain
F: VRC34_m228 Light Chain
A: VRC34_mm28 Heavy Chain
C: VRC34_mm28 Heavy Chain
G: VRC34_mm28 Heavy Chain
B: VRC34_m228 Light Chain
D: VRC34_m228 Light Chain
H: VRC34_m228 Light Chain
K: HIV-1 Env Fusion Peptide
L: HIV-1 Env Fusion Peptide
M: HIV-1 Env Fusion Peptide


Theoretical massNumber of molelcules
Total (without water)196,72412
Polymers196,72412
Non-polymers00
Water6,233346
1
I: HIV-1 Env Fusion Peptide
A: VRC34_mm28 Heavy Chain
B: VRC34_m228 Light Chain


Theoretical massNumber of molelcules
Total (without water)49,1813
Polymers49,1813
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4590 Å2
ΔGint-33 kcal/mol
Surface area18860 Å2
MethodPISA
2
E: VRC34_mm28 Heavy Chain
F: VRC34_m228 Light Chain
L: HIV-1 Env Fusion Peptide


Theoretical massNumber of molelcules
Total (without water)49,1813
Polymers49,1813
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4570 Å2
ΔGint-36 kcal/mol
Surface area18950 Å2
MethodPISA
3
C: VRC34_mm28 Heavy Chain
D: VRC34_m228 Light Chain
K: HIV-1 Env Fusion Peptide


Theoretical massNumber of molelcules
Total (without water)49,1813
Polymers49,1813
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4600 Å2
ΔGint-34 kcal/mol
Surface area18990 Å2
MethodPISA
4
G: VRC34_mm28 Heavy Chain
H: VRC34_m228 Light Chain
M: HIV-1 Env Fusion Peptide


Theoretical massNumber of molelcules
Total (without water)49,1813
Polymers49,1813
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4600 Å2
ΔGint-35 kcal/mol
Surface area18850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)129.850, 130.554, 130.589
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: Protein/peptide
HIV-1 Env Fusion Peptide


Mass: 718.863 Da / Num. of mol.: 4 / Source method: obtained synthetically / Source: (synth.) Human immunodeficiency virus 1
#2: Protein
VRC34_mm28 Heavy Chain


Mass: 25091.197 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody
VRC34_m228 Light Chain


Mass: 23371.021 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 346 / 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: 2.81 Å3/Da / Density % sol: 56.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 10% PEG 3350, 1.4M Na/K Phosphate pH 7.5

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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 10, 2022
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: 60434 / % possible obs: 97.85 % / Redundancy: 6.5 % / CC1/2: 0.991 / CC star: 0.998 / Rmerge(I) obs: 0.134 / Rpim(I) all: 0.057 / Rrim(I) all: 0.146 / Net I/σ(I): 16
Reflection shellResolution: 2.7→2.75 Å / Rmerge(I) obs: 0.581 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 3015 / CC1/2: 0.844 / CC star: 0.957 / Rpim(I) all: 0.238 / Rrim(I) all: 0.629

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Alphafold model

Resolution: 2.7→36.22 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 24.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2428 1995 3.32 %
Rwork0.2105 --
obs0.2116 60160 97.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.7→36.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12968 0 0 346 13314
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00613280
X-RAY DIFFRACTIONf_angle_d0.97318100
X-RAY DIFFRACTIONf_dihedral_angle_d17.6741836
X-RAY DIFFRACTIONf_chiral_restr0.0542072
X-RAY DIFFRACTIONf_plane_restr0.0062308
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.770.31741440.26713991X-RAY DIFFRACTION96
2.77-2.840.3321360.27534159X-RAY DIFFRACTION99
2.84-2.930.33541440.27344150X-RAY DIFFRACTION99
2.93-3.020.25941380.25094141X-RAY DIFFRACTION99
3.02-3.130.28551330.2414182X-RAY DIFFRACTION99
3.13-3.260.2921490.24534114X-RAY DIFFRACTION98
3.26-3.40.30541340.23953947X-RAY DIFFRACTION94
3.4-3.580.26871390.21824197X-RAY DIFFRACTION99
3.58-3.810.2291460.19234195X-RAY DIFFRACTION99
3.81-4.10.17251380.18554243X-RAY DIFFRACTION99
4.1-4.510.21481460.16734205X-RAY DIFFRACTION99
4.51-5.160.19981390.16224051X-RAY DIFFRACTION95
5.16-6.50.20651590.19654299X-RAY DIFFRACTION99
6.5-36.220.2411500.22244291X-RAY DIFFRACTION96

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