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- EMDB-46478: Cryo-EM structure of PGDM1400 Fab bound to HIV-1 BG505 DS-SOSIP.6... -

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Basic information

Entry
Database: EMDB / ID: EMD-46478
TitleCryo-EM structure of PGDM1400 Fab bound to HIV-1 BG505 DS-SOSIP.664 Env trimer
Map datasharpened
Sample
  • Complex: PGDM1400 Fab with HIV-1 BG505 DS-SOSIP.664 Env trimer
    • Protein or peptide: HIV-1 BG505 DS-SOSIP gp120
    • Protein or peptide: PGDM1400 heavy chain
    • Protein or peptide: PGDM1400 light chain
    • Protein or peptide: HIV-1 BG505 DS-SOSIP glycoprotein gp41
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHiV-1 / Vaccine / viral protein / Fab / antibody / glycan / V2-apex
Function / homology
Function and homology information


symbiont-mediated perturbation of host defense response / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell ...symbiont-mediated perturbation of host defense response / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / identical protein binding / 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: 3.44 Å
AuthorsKanai T / Morano NC / Shapiro L / Kwong PD / Gorman J
Funding support United States, 1 items
OrganizationGrant numberCountry
Other governmentZ01 BK 05021-01 LDV United States
CitationJournal: Cell Rep / Year: 2025
Title: Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage.
Authors: Rosemarie D Mason / Baoshan Zhang / Nicholas C Morano / Chen-Hsiang Shen / Krisha McKee / Ashley Heimann / Renguang Du / Alexandra F Nazzari / Shelby Hodges / Tapan Kanai / Bob C Lin / Mark ...Authors: Rosemarie D Mason / Baoshan Zhang / Nicholas C Morano / Chen-Hsiang Shen / Krisha McKee / Ashley Heimann / Renguang Du / Alexandra F Nazzari / Shelby Hodges / Tapan Kanai / Bob C Lin / Mark K Louder / Nicole A Doria-Rose / Tongqing Zhou / Lawrence Shapiro / Mario Roederer / Peter D Kwong / Jason Gorman /
Abstract: Broadly neutralizing antibodies (bNAbs) targeting the apex of the HIV-1-envelope (Env) trimer comprise the most potent category of HIV-1 bNAbs and have emerged as promising therapeutics. Here, we ...Broadly neutralizing antibodies (bNAbs) targeting the apex of the HIV-1-envelope (Env) trimer comprise the most potent category of HIV-1 bNAbs and have emerged as promising therapeutics. Here, we investigate the development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage and report cryo-EM structures at 3.4 Å resolution of PGDM1400 and of an improved PGT145 variant (PGT145-R100aS), each bound to the BG505 Env trimer. Cross-species-based engineering improves PGT145 IC breadth to near that of PGDM1400. Despite similar breadth and potency, the two antibodies differ in their residue-level interactions with important apex features, including N160 glycans and apex cavity, with residue 100i of PGT145 (sulfated tyrosine) penetrating ∼7 Å farther than residue 100i of PGDM1400 (aspartic acid). While apex-directed bNAbs from other donors use maturation pathways that often converge on analogous residue-level recognition, our results demonstrate that divergent residue-level recognition can occur within the same lineage, thereby enabling improved coverage of escape variants.
History
DepositionAug 8, 2024-
Header (metadata) releaseDec 25, 2024-
Map releaseDec 25, 2024-
UpdateFeb 5, 2025-
Current statusFeb 5, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46478.png

Downloads & links

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Map

FileDownload / File: emd_46478.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 512 pix.
= 424.96 Å		0.83 Å/pix.
x 512 pix.
= 424.96 Å		0.83 Å/pix.
x 512 pix.
= 424.96 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.14
Minimum - Maximum-1.0465322 - 1.3294513
Average (Standard dev.)0.00013398574 (±0.022419773)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 424.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46478_msk_1.map
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Additional map: resolve map

Fileemd_46478_additional_1.map
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Additional map: unsharpened

Fileemd_46478_additional_2.map
Annotationunsharpened
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Half map: half map A

Fileemd_46478_half_map_1.map
Annotationhalf map A
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Half map: half map B

Fileemd_46478_half_map_2.map
Annotationhalf map B
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Sample components

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Entire : PGDM1400 Fab with HIV-1 BG505 DS-SOSIP.664 Env trimer

EntireName: PGDM1400 Fab with HIV-1 BG505 DS-SOSIP.664 Env trimer
Components
  • Complex: PGDM1400 Fab with HIV-1 BG505 DS-SOSIP.664 Env trimer
    • Protein or peptide: HIV-1 BG505 DS-SOSIP gp120
    • Protein or peptide: PGDM1400 heavy chain
    • Protein or peptide: PGDM1400 light chain
    • Protein or peptide: HIV-1 BG505 DS-SOSIP glycoprotein gp41
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: PGDM1400 Fab with HIV-1 BG505 DS-SOSIP.664 Env trimer

SupramoleculeName: PGDM1400 Fab with HIV-1 BG505 DS-SOSIP.664 Env trimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Human immunodeficiency virus 1

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Macromolecule #1: HIV-1 BG505 DS-SOSIP gp120

MacromoleculeName: HIV-1 BG505 DS-SOSIP gp120 / type: protein_or_peptide / ID: 1 / 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 #2: PGDM1400 heavy chain

MacromoleculeName: PGDM1400 heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.441605 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QAQLTQSGPE VRKPGTSVKV SCKAPGNTLK TYDLHWVRSV PGQGLQWMGW ISHEGDKKVI VERFKAKVTI DWDRSTNTAY LQLSGLTSG DTAVYYCAKG SKHRLRDYAL (TYS)DDDGALNWA VDVDYLSNLE FWGQGTAVTV SSASTKGPSV FPLAPSS KS TSGGTAALGC ...String:
QAQLTQSGPE VRKPGTSVKV SCKAPGNTLK TYDLHWVRSV PGQGLQWMGW ISHEGDKKVI VERFKAKVTI DWDRSTNTAY LQLSGLTSG DTAVYYCAKG SKHRLRDYAL (TYS)DDDGALNWA VDVDYLSNLE FWGQGTAVTV SSASTKGPSV FPLAPSS KS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVD K KVEPKSCD

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Macromolecule #3: PGDM1400 light chain

MacromoleculeName: PGDM1400 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.093719 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DFVLTQSPHS LSVTPGESAS ISCKSSHSLI HGDRNNYLAW YVQKPGRSPQ LLIYLASSRA SGVPDRFSGS GSDKDFTLKI SRVETEDVG TYYCMQGRES PWTFGQGTKV DIKRTVAAPS VFIFPPSDEQ LKSGTASVVC LLNNFYPREA KVQWKVDNAL Q SGNSQESV ...String:
DFVLTQSPHS LSVTPGESAS ISCKSSHSLI HGDRNNYLAW YVQKPGRSPQ LLIYLASSRA SGVPDRFSGS GSDKDFTLKI SRVETEDVG TYYCMQGRES PWTFGQGTKV DIKRTVAAPS VFIFPPSDEQ LKSGTASVVC LLNNFYPREA KVQWKVDNAL Q SGNSQESV TEQDSKDSTY SLSSTLTLSK ADYEKHKVYA CEVTHQGLSS PVTKSFNRGE C

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Macromolecule #4: HIV-1 BG505 DS-SOSIP glycoprotein gp41

MacromoleculeName: HIV-1 BG505 DS-SOSIP glycoprotein gp41 / type: protein_or_peptide / ID: 4 / 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 #10: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 10 / Number of copies: 33 / 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

Concentration4 mg/mL
BufferpH: 7.5 / Details: PBS
GridModel: C-flat-1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Average exposure time: 2.5 sec. / Average electron dose: 58.06 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: 2.0 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 reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 162971
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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