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- EMDB-29248: Cryo-EM Structure of PG9RSH DU011 Fab in complex with BG505 DS-SO... -

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Basic information

Entry
Database: EMDB / ID: EMD-29248
TitleCryo-EM Structure of PG9RSH DU011 Fab in complex with BG505 DS-SOSIP.664
Map datasharpened map
Sample
  • Complex: Cryo-EM Structure of PG9RSH DU011 Fab in complex with BG505 DS-SOSIP.664
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Immunoblobulin G1 Fab heavy chain variable region (Fragment)
    • Protein or peptide: Immunoglobulin lambda-1 light chain-like
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsCD4 / HIV-1 / SOSIP / Vaccine / IMMUNE SYSTEM / llama / V2 apex / therapeutic / VIRAL PROTEIN
Function / homology
Function and homology information


immunoglobulin complex / immunoglobulin mediated immune response / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / antigen binding / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / blood microparticle / viral protein processing ...immunoglobulin complex / immunoglobulin mediated immune response / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / antigen binding / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / blood microparticle / viral protein processing / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / extracellular region / identical protein binding / plasma 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 / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain ...: / Envelope glycoprotein Gp160 / Retroviral envelope protein / Retroviral envelope protein GP41-like / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120 / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / : / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Immunoblobulin G1 Fab heavy chain variable region / Envelope glycoprotein gp160 / Ig-like domain-containing protein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsGorman J / Kwong PD
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
Other privateSimons Foundation (SF349247)
CitationJournal: Cell Rep / Year: 2023
Title: Improved HIV-1 neutralization breadth and potency of V2-apex antibodies by in silico design.
Authors: Graham T Holt / Jason Gorman / Siyu Wang / Anna U Lowegard / Baoshan Zhang / Tracy Liu / Bob C Lin / Mark K Louder / Marcel S Frenkel / Krisha McKee / Sijy O'Dell / Reda Rawi / Chen-Hsiang ...Authors: Graham T Holt / Jason Gorman / Siyu Wang / Anna U Lowegard / Baoshan Zhang / Tracy Liu / Bob C Lin / Mark K Louder / Marcel S Frenkel / Krisha McKee / Sijy O'Dell / Reda Rawi / Chen-Hsiang Shen / Nicole A Doria-Rose / Peter D Kwong / Bruce R Donald /
Abstract: Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency of neutralization. We employ ...Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency of neutralization. We employ the OSPREY computational protein design software to engineer variants of two apex-directed bNAbs, PGT145 and PG9RSH, resulting in increases in potency of over 100-fold against some viruses. The top designed variants improve neutralization breadth from 39% to 54% at clinically relevant concentrations (IC < 1 μg/mL) and improve median potency (IC) by up to 4-fold over a cross-clade panel of 208 strains. To investigate the mechanisms of improvement, we determine cryoelectron microscopy structures of each variant in complex with the HIV envelope trimer. Surprisingly, we find the largest increases in breadth to be a result of optimizing side-chain interactions with highly variable epitope residues. These results provide insight into mechanisms of neutralization breadth and inform strategies for antibody design and improvement.
History
DepositionDec 20, 2022-
Header (metadata) releaseMay 31, 2023-
Map releaseMay 31, 2023-
UpdateJul 26, 2023-
Current statusJul 26, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29248.png

Downloads & links

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Map

FileDownload / File: emd_29248.map.gz / Format: CCP4 / Size: 149.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 340 pix.
= 368.22 Å		1.08 Å/pix.
x 340 pix.
= 368.22 Å		1.08 Å/pix.
x 340 pix.
= 368.22 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.083 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-2.5512187 - 4.174928
Average (Standard dev.)0.0034691147 (±0.06186848)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 368.21997 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_29248_msk_1.map
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Additional map: unsharpened map

Fileemd_29248_additional_1.map
Annotationunsharpened map
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Additional map: Resolve density modified map

Fileemd_29248_additional_2.map
AnnotationResolve density modified map
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Half map: half map A

Fileemd_29248_half_map_1.map
Annotationhalf map A
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Histogram

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Half map: half map B

Fileemd_29248_half_map_2.map
Annotationhalf map B
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Sample components

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Entire : Cryo-EM Structure of PG9RSH DU011 Fab in complex with BG505 DS-SO...

EntireName: Cryo-EM Structure of PG9RSH DU011 Fab in complex with BG505 DS-SOSIP.664
Components
  • Complex: Cryo-EM Structure of PG9RSH DU011 Fab in complex with BG505 DS-SOSIP.664
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Immunoblobulin G1 Fab heavy chain variable region (Fragment)
    • Protein or peptide: Immunoglobulin lambda-1 light chain-like
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Cryo-EM Structure of PG9RSH DU011 Fab in complex with BG505 DS-SO...

SupramoleculeName: Cryo-EM Structure of PG9RSH DU011 Fab in complex with BG505 DS-SOSIP.664
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Human immunodeficiency virus 1

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Macromolecule #1: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 17.146482 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
AVGIGAVFLG FLGAAGSTMG AASMTLTVQA RNLLSGIVQQ QSNLLRAPEA QQHLLKLTVW GIKQLQARVL AVERYLRDQQ LLGIWGCSG KLICCTNVPW NSSWSNRNLS EIWDNMTWLQ WDKEISNYTQ IIYGLLEESQ NQQEKNEQDL LALD

UniProtKB: Envelope glycoprotein gp160

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Macromolecule #2: Envelope glycoprotein gp120

MacromoleculeName: Envelope glycoprotein gp120 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1 / Strain: BG505
Molecular weightTheoretical: 54.086324 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHTDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT ...String:
AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHTDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT SACTQACPKV SFEPIPIHYC APAGFAILKC KDKKFNGTGP CPSVSTVQCT HGIKPVVSTQ LLLNGSLAEE EV MIRSENI TNNAKNILVQ FNTPVQINCT RPNNNTRKSI RIGPGQAFYA TGDIIGDIRQ AHCNVSKATW NETLGKVVKQ LRK HFGNNT IIRFANSSGG DLEVTTHSFN CGGEFFYCNT SGLFNSTWIS NTSVQGSNST GSNDSITLPC RIKQIINMWQ RIGQ CMYAP PIQGVIRCVS NITGLILTRD GGSTNSTTET FRPGGGDMRD NWRSELYKYK VVKIEPLGVA PTRCKRRVVG RRRRR R

UniProtKB: Envelope glycoprotein gp160

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Macromolecule #3: Immunoblobulin G1 Fab heavy chain variable region (Fragment)

MacromoleculeName: Immunoblobulin G1 Fab heavy chain variable region (Fragment)
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.260258 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ERLVESGGGV VQPGSSLRLS CAASGFDFSR QGMHWVRQAP GQGLEWVAFI KYDGSEKYHA DSVWGRLSIS RDNSKDTLYL QMNSLRVED TATYFCVREA GGPDYRNGYY (TYS)(TYS)DFYDGYYN YHYMDVWGKG TTVTVSSAST KGPSVFPLAP SSK STSGGT ...String:
ERLVESGGGV VQPGSSLRLS CAASGFDFSR QGMHWVRQAP GQGLEWVAFI KYDGSEKYHA DSVWGRLSIS RDNSKDTLYL QMNSLRVED TATYFCVREA GGPDYRNGYY (TYS)(TYS)DFYDGYYN YHYMDVWGKG TTVTVSSAST KGPSVFPLAP SSK STSGGT AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDK KVEPK SCDKGLEVLF Q

UniProtKB: Immunoblobulin G1 Fab heavy chain variable region

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Macromolecule #4: Immunoglobulin lambda-1 light chain-like

MacromoleculeName: Immunoglobulin lambda-1 light chain-like / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.804182 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSALTQPASV SGSPGQSITI SCQGTSNDVG GYESVSWYQQ HPGKAPKVVI YDVSKRPSGV SNRFSGSKSG NTASLTISGL QAEDEGDYY CKSLTSRSHR VFGTGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPV K AGVETTTP ...String:
QSALTQPASV SGSPGQSITI SCQGTSNDVG GYESVSWYQQ HPGKAPKVVI YDVSKRPSGV SNRFSGSKSG NTASLTISGL QAEDEGDYY CKSLTSRSHR VFGTGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPV K AGVETTTP SKQSNNKYAA SSYLSLTPEQ WKSHKSYSCQ VTHEGSTVEK TVAPTECS

UniProtKB: Ig-like domain-containing protein

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 38 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration2 mg/mL
BufferpH: 7.4 / Details: PBS
GridModel: C-flat-1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Average exposure time: 2.0 sec. / Average electron dose: 63.75 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3) / Number images used: 230180
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationSoftware - Name: cryoSPARC (ver. 3)

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Atomic model buiding 1

Initial modelPDB ID:

6nnf

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8fk5:
Cryo-EM Structure of PG9RSH DU011 Fab in complex with BG505 DS-SOSIP.664

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