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- EMDB-29288: Cryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SO... -

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Basic information

Entry
Database: EMDB / ID: EMD-29288
TitleCryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SOSIP.664
Map datasharpened map
Sample
  • Complex: Cryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SOSIP.664
    • Protein or peptide: PGT145 DU303 Heavy
    • Protein or peptide: PGT145 DU303 Light
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: Envelope glycoprotein gp120
  • 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


positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / 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 ...positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / 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 / 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
Similarity search - Domain/homology
Envelope glycoprotein gp160
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.58 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 22, 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_29288.png

Downloads & links

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Map

FileDownload / File: emd_29288.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

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.083 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.8169878 - 3.3548636
Average (Standard dev.)0.0040237703 (±0.052132726)
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_29288_msk_1.map
Projections & Slices
AxesZYX

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Additional map: resolve density modified map

Fileemd_29288_additional_1.map
Annotationresolve density modified map
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Additional map: unsharpened map

Fileemd_29288_additional_2.map
Annotationunsharpened map
Projections & Slices
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Half map: half map A

Fileemd_29288_half_map_1.map
Annotationhalf map A
Projections & Slices
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Half map: half map B

Fileemd_29288_half_map_2.map
Annotationhalf map B
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Sample components

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Entire : Cryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SO...

EntireName: Cryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SOSIP.664
Components
  • Complex: Cryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SOSIP.664
    • Protein or peptide: PGT145 DU303 Heavy
    • Protein or peptide: PGT145 DU303 Light
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: Envelope glycoprotein gp120
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Cryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SO...

SupramoleculeName: Cryo-EM Structure of PGT145 DU303 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: PGT145 DU303 Heavy

MacromoleculeName: PGT145 DU303 Heavy / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.310439 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGAE VKKPGSSVKV SCKASGNSFS NHDVHWVRQA TGQGLEWMGW MSHEGDKTGL AQKFQGRVTI TRDSGASTVY MELRGLTAD DTAIYYCLTG SKHRLRDYFL (TYS)NE(TYS)GPDYEE WGDYLATLDV WGHGTAVTVS SASTKGPSVF PLA PSSKST ...String:
QVQLVQSGAE VKKPGSSVKV SCKASGNSFS NHDVHWVRQA TGQGLEWMGW MSHEGDKTGL AQKFQGRVTI TRDSGASTVY MELRGLTAD DTAIYYCLTG SKHRLRDYFL (TYS)NE(TYS)GPDYEE WGDYLATLDV WGHGTAVTVS SASTKGPSVF PLA PSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNT KVDKK VEPKSCDKGL EVLFQ

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Macromolecule #2: PGT145 DU303 Light

MacromoleculeName: PGT145 DU303 Light / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.95375 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVVITQSPLF LPVTPGEAAS LSCKCSHSLQ HSTGANYLAW YLQRPGQTPR LLIHLATHRA SGVPDRFSGS GSGTDFTLKI SRVESDDVG TYYCMQGLHS PWTFGQGTKV EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC LLNNFYPREA KVQWKVDNAL Q SGNSQESV ...String:
EVVITQSPLF LPVTPGEAAS LSCKCSHSLQ HSTGANYLAW YLQRPGQTPR LLIHLATHRA SGVPDRFSGS GSGTDFTLKI SRVESDDVG TYYCMQGLHS PWTFGQGTKV EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC LLNNFYPREA KVQWKVDNAL Q SGNSQESV TEQDSKDSTY SLSSTLTLSK ADYEKHKVYA CEVTHQGLSS PVTKSFNRGE C

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Macromolecule #3: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 3 / 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 #4: Envelope glycoprotein gp120

MacromoleculeName: Envelope glycoprotein gp120 / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
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 #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 35 / 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: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3) / Number images used: 107753
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-8flw:
Cryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SOSIP.664

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