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- EMDB-41417: Cryo-EM structure of HIV-1 Env BG505 DS-SOSIP in complex with bro... -

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Basic information

Entry
Database: EMDB / ID: EMD-41417
TitleCryo-EM structure of HIV-1 Env BG505 DS-SOSIP in complex with broadly neutralizing bi-specific antibody CAP256L-R27 targeting the CD4-binding site and the V2-apex
Map datacryo-EM density of bi-specific antibody CAP256L-R27 in complex with HIV-1 Env BG505 DS-SOSIP
Sample
  • Complex: Complex between HIV-1 Env BG505 DS-SOSIP and Bi-specific antibody CAP256L-R27
    • Protein or peptide: HIV-1 BG505 DS-SOSIP gp120
    • Protein or peptide: HIV-1 BG505 DS-SOSIP gp41
    • Protein or peptide: Light chain of bi-specific antibody CAP256L-R27
    • Protein or peptide: Heavy chain of bi-specific antibody CAP256L-R27
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHIV-1 Envelope / bi-specific / antibody / nanobody / VHH / llama / BG505 DS-SOSIP / neutralization / CAP256 / R27 / immunization / VIRAL PROTEIN-IMMUNE SYSTEM complex
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 / : / 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 / : / 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 speciesHomo sapiens (human) / Human immunodeficiency virus 1
Methodsingle particle reconstruction / cryo EM / Resolution: 3.61 Å
AuthorsZhou T / Morano NC / Roark RS / Kwong PD / Xu J
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Adv Sci (Weinh) / Year: 2024
Title: Ultrapotent Broadly Neutralizing Human-llama Bispecific Antibodies against HIV-1.
Authors: Jianliang Xu / Tongqing Zhou / Krisha McKee / Baoshan Zhang / Cuiping Liu / Alexandra F Nazzari / Amarendra Pegu / Chen-Hsiang Shen / Jordan E Becker / Michael F Bender / Payton Chan / Anita ...Authors: Jianliang Xu / Tongqing Zhou / Krisha McKee / Baoshan Zhang / Cuiping Liu / Alexandra F Nazzari / Amarendra Pegu / Chen-Hsiang Shen / Jordan E Becker / Michael F Bender / Payton Chan / Anita Changela / Ridhi Chaudhary / Xuejun Chen / Tal Einav / Young Do Kwon / Bob C Lin / Mark K Louder / Jonah S Merriam / Nicholas C Morano / Sijy O'Dell / Adam S Olia / Reda Rawi / Ryan S Roark / Tyler Stephens / I-Ting Teng / Emily Tourtellott-Fogt / Shuishu Wang / Eun Sung Yang / Lawrence Shapiro / Yaroslav Tsybovsky / Nicole A Doria-Rose / Rafael Casellas / Peter D Kwong /
Abstract: Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a ...Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion-stabilized HIV-1 envelope (Env) trimer, BG505 DS-SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4-binding site (CD4bs) of vulnerability. Two of the vaccine-elicited CD4bs-targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a-hinge region and human IgG1-constant region (G36×3-IgG2a and R27×3-IgG2a), neutralized 96% of a multiclade 208-strain panel at geometric mean ICs of 0.314 and 0.033 µg mL, respectively. Cryo-EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV-1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2-apex-targeting broadly neutralizing antibody, CAP256V2LS. The resultant human-llama bispecific antibody CAP256L-R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV-1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn-Fc mice similar to the parent CAP256V2LS. Vaccine-elicited llama nanobodies, when combined with V2-apex broadly neutralizing antibodies, may therefore be able to fulfill anti-HIV-1 therapeutic and prophylactic clinical goals.
History
DepositionAug 1, 2023-
Header (metadata) releaseMay 8, 2024-
Map releaseMay 8, 2024-
UpdateDec 18, 2024-
Current statusDec 18, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41417.png

Downloads & links

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Map

FileDownload / File: emd_41417.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo-EM density of bi-specific antibody CAP256L-R27 in complex with HIV-1 Env BG505 DS-SOSIP
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 500 pix.
= 415. Å		0.83 Å/pix.
x 500 pix.
= 415. Å		0.83 Å/pix.
x 500 pix.
= 415. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.225
Minimum - Maximum-0.29055202 - 0.9126448
Average (Standard dev.)0.0011173795 (±0.022514751)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions500500500
Spacing500500500
CellA=B=C: 415.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41417_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Sharpened cryo-EM map of bi-specific antibody CAP256L-R27 in...

Fileemd_41417_additional_1.map
AnnotationSharpened cryo-EM map of bi-specific antibody CAP256L-R27 in complex with HIV-1 Env BG505 DS-SOSIP
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: cryo-EM half map of bi-specific antibody CAP256L-R27 in...

Fileemd_41417_half_map_1.map
Annotationcryo-EM half map of bi-specific antibody CAP256L-R27 in complex with HIV-1 Env BG505 DS-SOSIP
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: cryo-EM half map of bi-specific antibody CAP256L-R27 in...

Fileemd_41417_half_map_2.map
Annotationcryo-EM half map of bi-specific antibody CAP256L-R27 in complex with HIV-1 Env BG505 DS-SOSIP
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex between HIV-1 Env BG505 DS-SOSIP and Bi-specific antibody...

EntireName: Complex between HIV-1 Env BG505 DS-SOSIP and Bi-specific antibody CAP256L-R27
Components
  • Complex: Complex between HIV-1 Env BG505 DS-SOSIP and Bi-specific antibody CAP256L-R27
    • Protein or peptide: HIV-1 BG505 DS-SOSIP gp120
    • Protein or peptide: HIV-1 BG505 DS-SOSIP gp41
    • Protein or peptide: Light chain of bi-specific antibody CAP256L-R27
    • Protein or peptide: Heavy chain of bi-specific antibody CAP256L-R27
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex between HIV-1 Env BG505 DS-SOSIP and Bi-specific antibody...

SupramoleculeName: Complex between HIV-1 Env BG505 DS-SOSIP and Bi-specific antibody CAP256L-R27
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 405 KDa

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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: HIV-1 BG505 DS-SOSIP gp41

MacromoleculeName: HIV-1 BG505 DS-SOSIP gp41 / type: protein_or_peptide / ID: 2 / 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 #3: Light chain of bi-specific antibody CAP256L-R27

MacromoleculeName: Light chain of bi-specific antibody CAP256L-R27 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.949734 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLQESGGG LVQPGGSLRL SCVASGFDLE NYSIGWFRQA PGKAREGVAC LSKNSGIGHS VKGRFTISRD GDSNTWFLQM GALEAEDTA VYTCATYNRA CANYVTIWPE FRGQGTQVTV SSGGSGGGGS GGGGSGGQSV LTQPPSVSAA PGQKVTISCS G NTSNIGNN ...String:
QVQLQESGGG LVQPGGSLRL SCVASGFDLE NYSIGWFRQA PGKAREGVAC LSKNSGIGHS VKGRFTISRD GDSNTWFLQM GALEAEDTA VYTCATYNRA CANYVTIWPE FRGQGTQVTV SSGGSGGGGS GGGGSGGQSV LTQPPSVSAA PGQKVTISCS G NTSNIGNN FVSWYQQRPG RAPQLLIYET DKRPSGIPDR FSASKSGTSG TLAITGLQTG DEADYYCATW AASLSSARVF GT GTQVIVL GQPKVNPTVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADSSPVK AGVETTTPSK QSNNKYAASS YLS LTPEQW KSHRSYSCQV THEGSTVEKT VAPTECS

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Macromolecule #4: Heavy chain of bi-specific antibody CAP256L-R27

MacromoleculeName: Heavy chain of bi-specific antibody CAP256L-R27 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.863039 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVESGGG VVQPGTSLRL SCAASQFRFD GYGMHWVRQA PGKGLEWVAS ISHDGIKKYH AEKVWGRFTI SRDNSKNTLY LQMNSLRPE DTALYYCAKD LREDECEEWW SD(TYS)(TYS)DFGAQL PCAKSRGGLV GIADNWGQGT MVTVSSASTK GPS VFPLAP ...String:
QVQLVESGGG VVQPGTSLRL SCAASQFRFD GYGMHWVRQA PGKGLEWVAS ISHDGIKKYH AEKVWGRFTI SRDNSKNTLY LQMNSLRPE DTALYYCAKD LREDECEEWW SD(TYS)(TYS)DFGAQL PCAKSRGGLV GIADNWGQGT MVTVSSASTK GPS VFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNH KPSNT KVDKKVEPKS

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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: 32 / 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

Concentration3 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE
DetailsPurified complex by FPLC and concentrated to final concentration.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
TemperatureMin: 70.0 K / Max: 100.0 K
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Average electron dose: 58.06 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 103000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1189143 / Details: Blob pick in cryoSparc
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8fis

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.61 Å / Resolution method: FSC 0.5 CUT-OFF / Software - Name: cryoSPARC (ver. 3) / Number images used: 236154
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

Initial modelPDB ID:

7lpn


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 82.9
Output model

PDB-8tni:
Cryo-EM structure of HIV-1 Env BG505 DS-SOSIP in complex with broadly neutralizing bi-specific antibody CAP256L-R27 targeting the CD4-binding site and the V2-apex

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