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- EMDB-41820: Cryo-EM structure of vaccine-elicited CD4 binding site antibody D... -

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Entry
Database: EMDB / ID: EMD-41820
TitleCryo-EM structure of vaccine-elicited CD4 binding site antibody DH1285 bound to HIV-1 CH505TFchim.6R.SOSIP.664v4.1 Env
Map dataCryo-EM structure of rhesus macaque vaccination elicited CD4 binding site antibody DH1285 Fab bound at two CD4 binding sites on CH505TFchim.6R.SOSIP.664v4.1 Env
Sample
  • Organelle or cellular component: A Complex of ectodomain of HIV-1 CH505TFchim.6R.SOSIP.664v4.1 Env with CD4 binding site antibody Dh1285 Fab in 1:3 ratio
KeywordsHIV-1 / CD4 binding site antibody / Vaccine elicited antibody / neutralizing antibody / IgG / Fab / DH1285 / VIRAL PROTEIN
Biological speciesHuman immunodeficiency virus 1
Methodsingle particle reconstruction / cryo EM / Resolution: 4.6 Å
AuthorsThakur B / Stalls VD / Acharya P
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 A1145687 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)UM1 A1144371 United States
CitationJournal: Cell / Year: 2024
Title: Vaccine induction of CD4-mimicking HIV-1 broadly neutralizing antibody precursors in macaques.
Authors: Kevin O Saunders / James Counts / Bhishem Thakur / Victoria Stalls / Robert Edwards / Kartik Manne / Xiaozhi Lu / Katayoun Mansouri / Yue Chen / Rob Parks / Maggie Barr / Laura Sutherland / ...Authors: Kevin O Saunders / James Counts / Bhishem Thakur / Victoria Stalls / Robert Edwards / Kartik Manne / Xiaozhi Lu / Katayoun Mansouri / Yue Chen / Rob Parks / Maggie Barr / Laura Sutherland / Joena Bal / Nicholas Havill / Haiyan Chen / Emily Machiele / Nolan Jamieson / Bhavna Hora / Megan Kopp / Katarzyna Janowska / Kara Anasti / Chuancang Jiang / Elizabeth Van Itallie / Sravani Venkatayogi / Amanda Eaton / Rory Henderson / Christopher Barbosa / S Munir Alam / Sampa Santra / Drew Weissman / M Anthony Moody / Derek W Cain / Ying K Tam / Mark Lewis / Wilton B Williams / Kevin Wiehe / David C Montefiori / Priyamvada Acharya / Barton F Haynes /
Abstract: The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs ...The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the occlusion of CD4bs by glycans, expansion of appropriate naive B cells with immunogens, and selection of functional antibody mutations. Here, we demonstrate that immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAb bound to HIV-1 Env demonstrated binding angles and heavy-chain interactions characteristic of all known human CD4-mimicking bnAbs. Macaque nAb were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAb. This vaccine study initiated in primates the B cells from which CD4bs bnAbs can derive, accomplishing the key first step in the development of an effective HIV-1 vaccine.
History
DepositionSep 1, 2023-
Header (metadata) releaseJan 3, 2024-
Map releaseJan 3, 2024-
UpdateJul 17, 2024-
Current statusJul 17, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41820.png

Downloads & links

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Map

FileDownload / File: emd_41820.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of rhesus macaque vaccination elicited CD4 binding site antibody DH1285 Fab bound at two CD4 binding sites on CH505TFchim.6R.SOSIP.664v4.1 Env
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.214
Minimum - Maximum-0.34464765 - 0.5694145
Average (Standard dev.)0.00039906826 (±0.01688142)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 345.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_41820_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_41820_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : A Complex of ectodomain of HIV-1 CH505TFchim.6R.SOSIP.664v4.1 Env...

EntireName: A Complex of ectodomain of HIV-1 CH505TFchim.6R.SOSIP.664v4.1 Env with CD4 binding site antibody Dh1285 Fab in 1:3 ratio
Components
  • Organelle or cellular component: A Complex of ectodomain of HIV-1 CH505TFchim.6R.SOSIP.664v4.1 Env with CD4 binding site antibody Dh1285 Fab in 1:3 ratio

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Supramolecule #1: A Complex of ectodomain of HIV-1 CH505TFchim.6R.SOSIP.664v4.1 Env...

SupramoleculeName: A Complex of ectodomain of HIV-1 CH505TFchim.6R.SOSIP.664v4.1 Env with CD4 binding site antibody Dh1285 Fab in 1:3 ratio
type: organelle_or_cellular_component / ID: 1 / Parent: 0
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 300 KDa

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.3 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 298 K / Instrument: LEICA EM CPC

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 59.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 14427340
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 146445
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC

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Atomic model buiding 1

RefinementSpace: REAL

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