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- EMDB-71308: eN49P7-FRv1-23 Fab in complex with BG505 MD39 SOSIP and RM20A3 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-71308
TitleeN49P7-FRv1-23 Fab in complex with BG505 MD39 SOSIP and RM20A3 Fab
Map datasharpened map
Sample
  • Complex: eN49P7-FRv1-23 Fab in complex with BG505 MD39 SOSIP and RM20A3 Fab
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: RM20A3 heavy chain
    • Protein or peptide: RM20A3 light chain
    • Protein or peptide: eN49P7-FRv1-23 heavy chain
    • Protein or peptide: eN49P7-FRv1-23 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsantibody engineering / HIV-1 / bnAb / broadly neutralizing antibody / CD4 binding site / Env / VIRAL PROTEIN
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 / membrane / identical protein binding
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 / Envelope glycoprotein gp160
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1 / Macaca mulatta (Rhesus monkey) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsPhulera S / Ozorowski G / Ward AB
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: bioRxiv / Year: 2025
Title: Engineering HIV antibodies with enhanced breadth and potency of neutralization through multistate affinity maturation.
Authors: Mateusz Kędzior / Swastik Phulera / Monica L Fernández-Quintero / Johannes R Loeffler / Collin Joyce / Jordan Woehl / Abdolrahim Abbasi / Maryam Karimi / Arash Aslanabadi / Mahsa Hojabri / ...Authors: Mateusz Kędzior / Swastik Phulera / Monica L Fernández-Quintero / Johannes R Loeffler / Collin Joyce / Jordan Woehl / Abdolrahim Abbasi / Maryam Karimi / Arash Aslanabadi / Mahsa Hojabri / Roza Zareidoodeji / Ben Atkinson / Eduar Fernando Pinzon Burgos / Alonso Heredia / Karen Saye-Francisco / Quoc Tran / Yoojin Kim / Fernando Acosta-Puente / Lara Shahin / Amelia Zhou / Pilar X Altman / Nathaniel R Felbinger / Brian G Pierce / Devin Sok / Michael S Seaman / Dennis R Burton / Anthony L DeVico / Andrew B Ward / Gabriel Ozorowski / Mohammad M Sajadi / Joseph G Jardine /
Abstract: Broadly neutralizing antibodies (bnAbs) against HIV hold promise as therapeutic and prophylactic agents, but realizing this potential requires antibodies that function across the antigenic ...Broadly neutralizing antibodies (bnAbs) against HIV hold promise as therapeutic and prophylactic agents, but realizing this potential requires antibodies that function across the antigenic heterogeneity of the HIV envelope glycoprotein (Env). Although numerous bnAbs have been isolated from infected individuals, their breadth and potency may not be sufficient to tackle global viral diversity, motivating efforts to further improve their neutralization capacity. Here, we address this challenge using a multistate antibody engineering approach integrating deep mutational scanning with combinatorial library screening across diverse Env variants. This strategy enables identification of mutation patterns that confer improved binding across antigenically distinct targets. Starting from one of the best-in-class CD4-binding site bnAbs, we performed iterative optimization to increase binding affinity across diverse Env variants. The resulting lead candidate exhibited improved breadth and up to 100-fold higher potency against pseudoviruses from large cross-clade historical and contemporary panels while maintaining biophysical and pharmacokinetic profiles conducive to clinical development. Structural and molecular dynamics analyses revealed a unique tri-tyrosine aromatic triad and reinforced electrostatic contacts that stabilized the bnAb/Env interface. These findings demonstrate that systematic engineering can generate bnAbs with enhanced breadth and potency, providing a generalizable strategy for developing therapeutic antibodies against highly diverse pathogens.
History
DepositionJun 19, 2025-
Header (metadata) releaseApr 29, 2026-
Map releaseApr 29, 2026-
UpdateApr 29, 2026-
Current statusApr 29, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71308.png

Downloads & links

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Map

FileDownload / File: emd_71308.map.gz / Format: CCP4 / Size: 244.1 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.)
1.03 Å/pix.
x 400 pix.
= 413.56 Å		1.03 Å/pix.
x 400 pix.
= 413.56 Å		1.03 Å/pix.
x 400 pix.
= 413.56 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0339 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-1.7710243 - 2.6479692
Average (Standard dev.)-0.00018066361 (±0.048188258)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 413.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_71308_msk_1.map
Projections & Slices
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Histogram (log scale)

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Half map: half map A

Fileemd_71308_half_map_1.map
Annotationhalf map A
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_71308_half_map_2.map
Annotationhalf map B
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Sample components

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Entire : eN49P7-FRv1-23 Fab in complex with BG505 MD39 SOSIP and RM20A3 Fab

EntireName: eN49P7-FRv1-23 Fab in complex with BG505 MD39 SOSIP and RM20A3 Fab
Components
  • Complex: eN49P7-FRv1-23 Fab in complex with BG505 MD39 SOSIP and RM20A3 Fab
    • Protein or peptide: Envelope glycoprotein gp120
    • Protein or peptide: Envelope glycoprotein gp41
    • Protein or peptide: RM20A3 heavy chain
    • Protein or peptide: RM20A3 light chain
    • Protein or peptide: eN49P7-FRv1-23 heavy chain
    • Protein or peptide: eN49P7-FRv1-23 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: eN49P7-FRv1-23 Fab in complex with BG505 MD39 SOSIP and RM20A3 Fab

SupramoleculeName: eN49P7-FRv1-23 Fab in complex with BG505 MD39 SOSIP and RM20A3 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Human immunodeficiency virus 1

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Macromolecule #1: Envelope glycoprotein gp120

MacromoleculeName: Envelope glycoprotein gp120 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 54.088289 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHEDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT ...String:
AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHEDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT SAITQACPKV SFEPIPIHYC APAGFAILKC KDKKFNGTGP CPSVSTVQCT HGIKPVVSTQ LLLNGSLAEE EV IIRSENI TNNAKNILVQ LNTPVQINCT RPNNNTVKSI RIGPGQAFYY TGDIIGDIRQ AHCNVSKATW NETLGKVVKQ LRK HFGNNT IIRFAQSSGG DLEVTTHSFN CGGEFFYCNT SGLFNSTWIS NTSVQGSNST GSNDSITLPC RIKQIINMWQ RIGQ AMYAP PIQGVIRCVS NITGLILTRD GGSTNSTTET FRPGGGDMRD NWRSELYKYK VVKIEPLGVA PTRCKRRVVG RRRRR R

UniProtKB: Envelope glycoprotein gp160

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Macromolecule #2: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 17.134324 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
AVGIGAVSLG FLGAAGSTMG AASMTLTVQA RNLLSGIVQQ QSNLLRAPEP QQHLLKDTHW GIKQLQARVL AVEHYLRDQQ LLGIWGCSG KLICCTNVPW NSSWSNRNLS EIWDNMTWLQ WDKEISNYTQ IIYGLLEESQ NQQEKNEQDL LALD

UniProtKB: Envelope glycoprotein gp160

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Macromolecule #3: RM20A3 heavy chain

MacromoleculeName: RM20A3 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
Molecular weightTheoretical: 13.511111 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLVETGGG LVQPGGSLKL SCRASGYTFS SFAMSWVRQA PGKGLEWVSL INDRGGLTFY VDSVKGRFTI SRDNSKNTLS LQMHSLRDG DTAVYYCATG GMSSALQSSK YYFDFWGQGA LVTVSS

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Macromolecule #4: RM20A3 light chain

MacromoleculeName: RM20A3 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Macaca mulatta (Rhesus monkey)
Molecular weightTheoretical: 11.540614 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
ALTQPPSVSG SPGQSVTISC TGTSSDIGSY NYVSWYQQHP GKAPKLMIYD VTQRPSGVSD RFSGSKSGNT ASLTISGLQA DDEADYYCS AYAGRQTFYI FGGGTRLTVL

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Macromolecule #5: eN49P7-FRv1-23 heavy chain

MacromoleculeName: eN49P7-FRv1-23 heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.432193 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
ADLVQSGAVT KKPGDSVRIS CEAQGYRFTD YFIHWIRQAP GKGPEWMGWI NPYYGQVNIP WKFQGRISMT RQRSQDPYDP DWGTAFLDL RGLKSDDTAV YYCVRDRSSG YGKLFESDNW FLDLWGRGTA VTIQS

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Macromolecule #6: eN49P7-FRv1-23 light chain

MacromoleculeName: eN49P7-FRv1-23 light chain / type: protein_or_peptide / ID: 6 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.855144 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QSALTQPNYV SALPGQSVTI SCTGTHNLVS WLQHQPGRAP KLLIYDFNKR PPGVPDRFSG SGSGGTASLT ITGLQLDDEA EYWCFAYEV FGGGTKLTVL MQ

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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: 36 / 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

BufferpH: 5.9
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 20.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 190000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: cryosparc ab initio
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 212503
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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