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- EMDB-21208: Cryo-EM structure of VRC01.23 in complex with HIV-1 Env BG505 DS.SOSIP -

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Basic information

Entry
Database: EMDB / ID: EMD-21208
TitleCryo-EM structure of VRC01.23 in complex with HIV-1 Env BG505 DS.SOSIP
Map dataSharpened Map at 3.4A resolution
Sample
  • Complex: HIV-1 Env BG505 DS-SOSIP and antibodies VRC01.23
    • Complex: BG505 DS.SOSIP with antibody VRC01.23 Fab
      • Protein or peptide: Envelope glycoprotein gp41
      • Protein or peptide: BG505 gp120
      • Protein or peptide: VRC01.23 Light chain
      • Protein or peptide: VRC01.23 Heavy chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
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 / virus-mediated perturbation of host defense response / 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 / virus-mediated perturbation of host defense response / 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 / structural molecule activity / virion attachment to host cell / host cell plasma membrane / 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: 3.43 Å
AuthorsGorman J / Kwong PD
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
CitationJournal: MAbs / Year: 2021
Title: A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention.
Authors: Young D Kwon / Mangaiarkarasi Asokan / Jason Gorman / Baoshan Zhang / Qingbo Liu / Mark K Louder / Bob C Lin / Krisha McKee / Amarendra Pegu / Raffaello Verardi / Eun Sung Yang / Vrc ...Authors: Young D Kwon / Mangaiarkarasi Asokan / Jason Gorman / Baoshan Zhang / Qingbo Liu / Mark K Louder / Bob C Lin / Krisha McKee / Amarendra Pegu / Raffaello Verardi / Eun Sung Yang / Vrc Production Program / Kevin Carlton / Nicole A Doria-Rose / Paolo Lusso / John R Mascola / Peter D Kwong /
Abstract: Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve ...Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve VRC01-class antibodies, we combined structure-based design with a matrix-based approach to generate VRC01-class variants that filled an interfacial cavity, used diverse third-complementarity-determining regions, reduced potential steric clashes, or exploited extended contacts to a neighboring protomer within the envelope trimer. On a 208-strain panel, variant VRC01.23LS neutralized 90% of the panel at a geometric mean IC less than 1 μg/ml, and in transgenic mice with human neonatal-Fc receptor, the serum half-life of VRC01.23LS was indistinguishable from that of the parent VRC01LS, which has a half-life of 71 d in humans. A cryo-electron microscopy structure of VRC01.23 Fab in complex with BG505 DS-SOSIP.664 Env trimer determined at 3.4-Å resolution confirmed the structural basis for its ~10-fold improved potency relative to VRC01. Another variant, VRC07-523-F54-LS.v3, neutralized 95% of the 208-isolated panel at a geometric mean IC of less than 1 μg/ml, with a half-life comparable to that of the parental VRC07-523LS. Our matrix-based structural approach thus enables the engineering of VRC01 variants for HIV-1 therapy and prevention with improved potency, breadth, and pharmacokinetics.
History
DepositionJan 10, 2020-
Header (metadata) releaseJan 13, 2021-
Map releaseJan 13, 2021-
UpdateAug 25, 2021-
Current statusAug 25, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6vi0
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6vi0
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21208.png

Downloads & links

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Map

FileDownload / File: emd_21208.map.gz / Format: CCP4 / Size: 115.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened Map at 3.4A resolution
Voxel sizeX=Y=Z: 1.07325 Å
Density
Contour LevelBy AUTHOR: 0.5 / Movie #1: 0.5
Minimum - Maximum-1.4865556 - 3.5287926
Average (Standard dev.)0.012745068 (±0.09422194)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions312312312
Spacing312312312
CellA=B=C: 334.854 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.073251.073251.07325
M x/y/z312312312
origin x/y/z0.0000.0000.000
length x/y/z334.854334.854334.854
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS312312312
D min/max/mean-1.4873.5290.013

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Supplemental data

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Mask #1

Fileemd_21208_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened Map

Fileemd_21208_additional_1.map
AnnotationUnsharpened Map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_21208_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_21208_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : HIV-1 Env BG505 DS-SOSIP and antibodies VRC01.23

EntireName: HIV-1 Env BG505 DS-SOSIP and antibodies VRC01.23
Components
  • Complex: HIV-1 Env BG505 DS-SOSIP and antibodies VRC01.23
    • Complex: BG505 DS.SOSIP with antibody VRC01.23 Fab
      • Protein or peptide: Envelope glycoprotein gp41
      • Protein or peptide: BG505 gp120
      • Protein or peptide: VRC01.23 Light chain
      • Protein or peptide: VRC01.23 Heavy chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: HIV-1 Env BG505 DS-SOSIP and antibodies VRC01.23

SupramoleculeName: HIV-1 Env BG505 DS-SOSIP and antibodies VRC01.23 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: BG505 DS.SOSIP with antibody VRC01.23 Fab

SupramoleculeName: BG505 DS.SOSIP with antibody VRC01.23 Fab / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#4
Source (natural)Organism: Human immunodeficiency virus 1
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Envelope glycoprotein gp41

MacromoleculeName: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 1 / 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

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Macromolecule #2: BG505 gp120

MacromoleculeName: BG505 gp120 / type: protein_or_peptide / ID: 2 / 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

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Macromolecule #3: VRC01.23 Light chain

MacromoleculeName: VRC01.23 Light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.761166 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LTQSPGTLSL SPGETAIISC RTSQYGSLAW YQQRPGQAPR LVIYSGSTRA AGIPDRFSGS RWGPDYNLTI SNLESGDFGV YYCQQYEFF GQGTKVQVDI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ D SKDSTYSL ...String:
LTQSPGTLSL SPGETAIISC RTSQYGSLAW YQQRPGQAPR LVIYSGSTRA AGIPDRFSGS RWGPDYNLTI SNLESGDFGV YYCQQYEFF GQGTKVQVDI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ D SKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

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Macromolecule #4: VRC01.23 Heavy chain

MacromoleculeName: VRC01.23 Heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.1094 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGGQ MKKPGESMRI SCRASGYEFI DCTLNWIRLA PGKRPEWMGW LKPRWGAVNY ARPLQGRVTM TRQLSQDPDD PDWGTAFLE LRSLTVDDTA VYFCTRGKNC DYNWDFEHWG RGTPVIVSSP STKGPSVFPL APSSKSTSGG TAALGCLVKD Y FPEPVTVS ...String:
QVQLVQSGGQ MKKPGESMRI SCRASGYEFI DCTLNWIRLA PGKRPEWMGW LKPRWGAVNY ARPLQGRVTM TRQLSQDPDD PDWGTAFLE LRSLTVDDTA VYFCTRGKNC DYNWDFEHWG RGTPVIVSSP STKGPSVFPL APSSKSTSGG TAALGCLVKD Y FPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP K

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Macromolecule #11: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 11 / Number of copies: 36 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

Concentration1.0 mg/mL
BufferpH: 7.4 / Component - Formula: PBS
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 1882 / Average exposure time: 10.0 sec. / Average electron dose: 70.41 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 153590
CTF correctionSoftware - Name: CTFFIND (ver. 4)
Initial angle assignmentType: NOT APPLICABLE
Final 3D classificationSoftware - Name: cryoSPARC (ver. 2.12)
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.43 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.12) / Number images used: 55046

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Atomic model buiding 1

Initial modelPDB ID:

6nnf

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6vi0:
Cryo-EM structure of VRC01.23 in complex with HIV-1 Env BG505 DS.SOSIP

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