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- EMDB-19164: Trimeric HSV-1F gB ectodomain in postfusion conformation with thr... -

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Basic information

Entry
Database: EMDB / ID: EMD-19164
TitleTrimeric HSV-1F gB ectodomain in postfusion conformation with three bound HDIT102 Fab molecules.
Map datafinal sharpened map
Sample
  • Complex: Trimeric HSV-1F gB ectodomain in post-fusion conformation with three bound HDIT102 Fab molecules
    • Protein or peptide: Envelope glycoprotein B
    • Protein or peptide: HDIT102 Fab heavy chain
    • Protein or peptide: HDIT102 Fab heavy chain
Keywordsectodomain / post-fusion / fab molecule / trimeric / VIRAL PROTEIN
Function / homology
Function and homology information


host cell Golgi membrane / host cell endosome membrane / symbiont entry into host cell / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Herpesvirus Glycoprotein B / Herpesvirus Glycoprotein B, PH-like domain 1 / Herpesvirus Glycoprotein B, PH-like domain 2 / Herpesvirus Glycoprotein B, PH-like domain 2 superfamily / Herpesvirus Glycoprotein B ectodomain / Herpesvirus Glycoprotein B / Herpesvirus Glycoprotein B PH-like domain
Similarity search - Domain/homology
Envelope glycoprotein B
Similarity search - Component
Biological speciesHomo sapiens (human) / Human alphaherpesvirus 1 (Herpes simplex virus type 1)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.44 Å
AuthorsKalbermatter D / Seyfizadeh N / Imhof T / Ries M / Mueller C / Jenner L / Blumenschein E / Yendrzheyevskiy A / Moog K / Eckert D ...Kalbermatter D / Seyfizadeh N / Imhof T / Ries M / Mueller C / Jenner L / Blumenschein E / Yendrzheyevskiy A / Moog K / Eckert D / Engel R / Diebolder P / Chami M / Krauss J / Schaller T / Arndt M
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: J Biomed Sci / Year: 2024
Title: Development of a highly effective combination monoclonal antibody therapy against Herpes simplex virus.
Authors: Narges Seyfizadeh / David Kalbermatter / Thomas Imhof / Moritz Ries / Christian Müller / Leonie Jenner / Elisabeth Blumenschein / Alexandra Yendrzheyevskiy / Frank Grün / Kevin Moog / ...Authors: Narges Seyfizadeh / David Kalbermatter / Thomas Imhof / Moritz Ries / Christian Müller / Leonie Jenner / Elisabeth Blumenschein / Alexandra Yendrzheyevskiy / Frank Grün / Kevin Moog / Daniel Eckert / Ronja Engel / Philipp Diebolder / Mohamed Chami / Jürgen Krauss / Torsten Schaller / Michaela Arndt /
Abstract: BACKGROUND: Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum ...BACKGROUND: Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum of pathology. Monoclonal antibody therapy has great potential especially to treat infections with virus resistant to standard therapies. HDIT101, a humanized IgG targeting HSV-1/2 gB was previously investigated in phase 2 clinical trials. The aim of this study was to develop a next-generation therapy by combining different antiviral monoclonal antibodies.
METHODS: A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using ...METHODS: A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using bio-layer interferometry. HDIT102 was further developed as fully human IgG and tested alone or in combination with HDIT101, a clinically tested humanized anti-HSV IgG, in vitro and in vivo. T-cell stimulating activities by antigen-presenting cells treated with IgG-HSV immune complexes were analyzed using primary human cells. To determine the epitopes, the cryo-EM structures of HDIT101 or HDIT102 Fab bound to HSV-1F as well as HSV-2G gB protein were solved at resolutions < 3.5 Å.
RESULTS: HDIT102 Fab showed strong binding to HSV-1F gB with Kd of 8.95 × 10 M and to HSV-2G gB with Kd of 3.29 × 10 M. Neutralization of cell-free virus and inhibition of cell-to-cell ...RESULTS: HDIT102 Fab showed strong binding to HSV-1F gB with Kd of 8.95 × 10 M and to HSV-2G gB with Kd of 3.29 × 10 M. Neutralization of cell-free virus and inhibition of cell-to-cell spread were comparable between HDIT101 and HDIT102. Both antibodies induced internalization of gB from the cell surface into acidic endosomes by binding distinct epitopes in domain I of gB and compete for binding. CryoEM analyses revealed the ability to form heterogenic immune complexes consisting of two HDIT102 and one HDIT101 Fab bound to one gB trimeric molecule. Both antibodies mediated antibody-dependent phagocytosis by antigen presenting cells which stimulated autologous T-cell activation. In vivo, the combination of HDIT101 and HDIT102 demonstrated synergistic effects on survival and clinical outcome in immunocompetent BALB/cOlaHsd mice.
CONCLUSION: This biochemical and immunological study showcases the potential of an effective combination therapy with two monoclonal anti-gB IgGs for the treatment of HSV-1/2 induced disease conditions.
History
DepositionDec 14, 2023-
Header (metadata) releaseJun 19, 2024-
Map releaseJun 19, 2024-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19164.png

Downloads & links

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Map

FileDownload / File: emd_19164.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationfinal sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.2 Å/pix.
x 300 pix.
= 360.84 Å		1.2 Å/pix.
x 300 pix.
= 360.84 Å		1.2 Å/pix.
x 300 pix.
= 360.84 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.2028 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0175
Minimum - Maximum-0.06906364 - 0.13405983
Average (Standard dev.)0.00015561124 (±0.002478703)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 360.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_19164_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_19164_half_map_1.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_19164_half_map_2.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Trimeric HSV-1F gB ectodomain in post-fusion conformation with th...

EntireName: Trimeric HSV-1F gB ectodomain in post-fusion conformation with three bound HDIT102 Fab molecules
Components
  • Complex: Trimeric HSV-1F gB ectodomain in post-fusion conformation with three bound HDIT102 Fab molecules
    • Protein or peptide: Envelope glycoprotein B
    • Protein or peptide: HDIT102 Fab heavy chain
    • Protein or peptide: HDIT102 Fab heavy chain

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Supramolecule #1: Trimeric HSV-1F gB ectodomain in post-fusion conformation with th...

SupramoleculeName: Trimeric HSV-1F gB ectodomain in post-fusion conformation with three bound HDIT102 Fab molecules
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 523 KDa

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Macromolecule #1: Envelope glycoprotein B

MacromoleculeName: Envelope glycoprotein B / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human alphaherpesvirus 1 (Herpes simplex virus type 1)
Molecular weightTheoretical: 100.449375 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRQGAPARGC RWFVVWALLG LTLGVLVASA APSSPGTPGV AAATQAANGG PATPAPPAPG PAPTGDTKPK KNKKPKNPPP PRPAGDNAT VAAGHATLRE HLRDIKAENT DANFYVCPPP TGATVVQFEQ PRRCPTRPEG QNYTEGIAVV FKENIAPYKF K ATMYYKDV ...String:
MRQGAPARGC RWFVVWALLG LTLGVLVASA APSSPGTPGV AAATQAANGG PATPAPPAPG PAPTGDTKPK KNKKPKNPPP PRPAGDNAT VAAGHATLRE HLRDIKAENT DANFYVCPPP TGATVVQFEQ PRRCPTRPEG QNYTEGIAVV FKENIAPYKF K ATMYYKDV TVSQVWFGHR YSQFMGIFED RAPVPFEEVI DKINAKGVCR STAKYVRNNL ETTAFHRDDH ETDMELKPAN AA TRTSRGW HTTDLKYNPS RVEAFHRYGT TVNCIVEEVD ARSVYPYDEF VLATGDFVYM SPFYGYREGS HTEHTSYAAD RFK QVDGFY ARDLTTKARA TAPTTRNLLT TPKFTVAWDW VPKRPSVCTM TKWQEVDEML RSEYGGSFRF SSDAISTTFT TNLT EYPLS RVDLGDCIGK DARDAMDRIF ARRYNATHIK VGQPQYYLAN GGFLIAYQPL LSNTLAELYV REHLREQSRK PPNPT PPPP GASANASVER IKTTSSIEFA RLQFTYNHIQ RHVNDMLGRV AIAWCELQNH ELTLWNEARK LNPNAIASAT VGRRVS ARM LGDVMAVSTC VPVAADNVIV QNSMRISSRP GACYSRPLVS FRYEDQGPLV EGQLGENNEL RLTRDAIEPC TVGHRRY FT FGGGYVYFEE YAYSHQLSRA DITTVSTFID LNITMLEDHE FVPLEVYTRH EIKDSGLLDY TEVQRRNQLH DLRFADID T VIHADANAAM FAGLGAFFEG MGDLGRAVGK VVMGIVGGVV SAVSGVSSFM SNPFGALAVG LLVLAGLAAA FFAFRYVMR LQSNPMKALY PLTTKELKNP TNPDASGEGE EGGDFDEAKL AEAREMIRYM ALVSAMEHTE HKAKKKGTSA LLSAKVTDMV MRKRRNTNY TQVPNKDGDA DEDDLAA

UniProtKB: Envelope glycoprotein B

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Macromolecule #2: HDIT102 Fab heavy chain

MacromoleculeName: HDIT102 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.310387 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVQSGAE VKTPGASVRV SCKASGHTFR TFDINWVRQA AGQGLEWMGW MSPNSGNTGY ARQFQGRVTM TRNISANTAY MELRGLRFD DTAVYYCARG PGSTGTTGSM DVWGQGTTVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
EVQLVQSGAE VKTPGASVRV SCKASGHTFR TFDINWVRQA AGQGLEWMGW MSPNSGNTGY ARQFQGRVTM TRNISANTAY MELRGLRFD DTAVYYCARG PGSTGTTGSM DVWGQGTTVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCDKT HTCPPCPAPE LL GGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD WLN GKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL PPSRDELTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTP PVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK

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Macromolecule #3: HDIT102 Fab heavy chain

MacromoleculeName: HDIT102 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.403775 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QAGLTQPPSV SVAPGKTARI SCGGNNIGSK SVHWYQQKPG QAPVLVIYYD SDRPSGIPER FSGSNSGNTA TLTISRVEAG DEADYYCQV WDSGSVVFGG GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS ...String:
QAGLTQPPSV SVAPGKTARI SCGGNNIGSK SVHWYQQKPG QAPVLVIYYD SDRPSGIPER FSGSNSGNTA TLTISRVEAG DEADYYCQV WDSGSVVFGG GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS

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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: 8
Component:
ConcentrationFormulaName
150.0 mMNaClSodium Chloride
50.0 mMC4H11NO3Tris
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 85 % / Chamber temperature: 283.15 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 6611 / Average exposure time: 4.0 sec. / Average electron dose: 1.15 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1059496
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

2gum

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 208280
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4.0)
Final 3D classificationSoftware - Name: RELION (ver. 4.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

2gum


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-8rh0:
Trimeric HSV-1F gB ectodomain in postfusion conformation with three bound HDIT102 Fab molecules.

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