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- EMDB-23465: Structure of CD4 mimetic M48U1 in complex with BG505 SOSIP.664 HI... -

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Basic information

Entry
Database: EMDB / ID: EMD-23465
TitleStructure of CD4 mimetic M48U1 in complex with BG505 SOSIP.664 HIV-1 Env trimer and 17b Fab
Map dataMap of CD4 mimetic M48U1 in complex with BG505 SOSIP.664 Env and 17b Fab
Sample
  • Complex: Human immunodeficiency virus 1
    • Complex: 17b antibody Fab
      • Protein or peptide: 17b Fab Light Chain
      • Protein or peptide: 17b Fab Heavy Chain
    • Complex: M48U1
      • Protein or peptide: M48U1
    • Complex: BG505 SOSIP.664 Env
      • Protein or peptide: Envelope glycoprotein BG505 SOSIP.664 gp120
      • Protein or peptide: Envelope Glycoprotein BG505 SOSIP.664 gp41
  • 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 / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / 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 / virus-mediated perturbation of host defense response / 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) / Leiurus quinquestriatus hebraeus (scorpion) / Human immunodeficiency virus 1
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsJette CA / Bjorkman PJ
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)2 P50 AI150464 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HIVRAD P01 AI100148 United States
CitationJournal: Nat Commun / Year: 2021
Title: Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation.
Authors: Claudia A Jette / Christopher O Barnes / Sharon M Kirk / Bruno Melillo / Amos B Smith / Pamela J Bjorkman /
Abstract: Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. Entry into target cells is mediated by the HIV-1 envelope (Env) glycoprotein interacting with host ...Human immunodeficiency virus-1 (HIV-1), the causative agent of AIDS, impacts millions of people. Entry into target cells is mediated by the HIV-1 envelope (Env) glycoprotein interacting with host receptor CD4, which triggers conformational changes allowing binding to a coreceptor and subsequent membrane fusion. Small molecule or peptide CD4-mimetic drugs mimic CD4's Phe43 interaction with Env by inserting into the conserved Phe43 pocket on Env subunit gp120. Here, we present single-particle cryo-EM structures of CD4-mimetics BNM-III-170 and M48U1 bound to a BG505 native-like Env trimer plus the CD4-induced antibody 17b at 3.7 Å and 3.9 Å resolution, respectively. CD4-mimetic-bound BG505 exhibits canonical CD4-induced conformational changes including trimer opening, formation of the 4-stranded gp120 bridging sheet, displacement of the V1V2 loop, and formation of a compact and elongated gp41 HR1C helical bundle. We conclude that CD4-induced structural changes on both gp120 and gp41 Env subunits are induced by binding to the gp120 Phe43 pocket.
History
DepositionFeb 10, 2021-
Header (metadata) releaseApr 14, 2021-
Map releaseApr 14, 2021-
UpdateApr 14, 2021-
Current statusApr 14, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7lok
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23465.png

Downloads & links

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Map

FileDownload / File: emd_23465.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap of CD4 mimetic M48U1 in complex with BG505 SOSIP.664 Env and 17b Fab
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 282.624 Å		1.1 Å/pix.
x 256 pix.
= 282.624 Å		1.1 Å/pix.
x 256 pix.
= 282.624 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.104 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015 / Movie #1: 0.015
Minimum - Maximum-0.053668063 - 0.091820255
Average (Standard dev.)0.00036653026 (±0.0027062816)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 282.624 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.1041.1041.104
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z282.624282.624282.624
α/β/γ90.00090.00090.000
start NX/NY/NZ645365
NX/NY/NZ139143124
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0540.0920.000

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Supplemental data

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Sample components

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Entire : Human immunodeficiency virus 1

EntireName: Human immunodeficiency virus 1
Components
  • Complex: Human immunodeficiency virus 1
    • Complex: 17b antibody Fab
      • Protein or peptide: 17b Fab Light Chain
      • Protein or peptide: 17b Fab Heavy Chain
    • Complex: M48U1
      • Protein or peptide: M48U1
    • Complex: BG505 SOSIP.664 Env
      • Protein or peptide: Envelope glycoprotein BG505 SOSIP.664 gp120
      • Protein or peptide: Envelope Glycoprotein BG505 SOSIP.664 gp41
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Human immunodeficiency virus 1

SupramoleculeName: Human immunodeficiency virus 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Details: BG505 SOSIP.664 Env trimer in complex with CD4 mimetic M48U1 and 17b Fab

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Supramolecule #2: 17b antibody Fab

SupramoleculeName: 17b antibody Fab / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293

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Supramolecule #3: M48U1

SupramoleculeName: M48U1 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #5 / Details: Synthetic peptide, CD4 mimetic
Source (natural)Organism: Leiurus quinquestriatus hebraeus (scorpion)

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Supramolecule #4: BG505 SOSIP.664 Env

SupramoleculeName: BG505 SOSIP.664 Env / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Human immunodeficiency virus 1 / Strain: BG505
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293

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Macromolecule #1: Envelope glycoprotein BG505 SOSIP.664 gp120

MacromoleculeName: Envelope glycoprotein BG505 SOSIP.664 gp120 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 53.864086 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NLWVTVYYGV PVWKDAETTL FCASDAKAYE TEKHNVWATH ACVPTDPNPQ EIHLENVTEE FNMWKNNMVE QMHTDIISLW DQSLKPCVK LTPLCVTLQC TNVTNNITDD MRGELKNCSF NMTTELRDKK QKVYSLFYRL DVVQINENQG NRSNNSNKEY R LINCNTSA ...String:
NLWVTVYYGV PVWKDAETTL FCASDAKAYE TEKHNVWATH ACVPTDPNPQ EIHLENVTEE FNMWKNNMVE QMHTDIISLW DQSLKPCVK LTPLCVTLQC TNVTNNITDD MRGELKNCSF NMTTELRDKK QKVYSLFYRL DVVQINENQG NRSNNSNKEY R LINCNTSA ITQACPKVSF EPIPIHYCAP AGFAILKCKD KKFNGTGPCP SVSTVQCTHG IKPVVSTQLL LNGSLAEEEV MI RSENITN NAKNILVQFN TPVQINCTRP NNNTRKSIRI GPGQAFYATG DIIGDIRQAH CNVSKATWNE TLGKVVKQLR KHF GNNTII RFANSSGGDL EVTTHSFNCG GEFFYCNTSG LFNSTWISNT SVQGSNSTGS NDSITLPCRI KQIINMWQRI GQAM YAPPI QGVIRCVSNI TGLILTRDGG STNSTTETFR PGGGDMRDNW RSELYKYKVV KIEPLGVAPT RCKRRVVGRR RRRR

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Macromolecule #2: Envelope Glycoprotein BG505 SOSIP.664 gp41

MacromoleculeName: Envelope Glycoprotein BG505 SOSIP.664 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

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Macromolecule #3: 17b Fab Light Chain

MacromoleculeName: 17b Fab Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.399898 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIVMTQSPAT LSVSPGERAT LSCRASESVS SDLAWYQQKP GQAPRLLIYG ASTRATGVPA RFSGSGSGAE FTLTISSLQS EDFAVYYCQ QYNNWPPRYT FGQGTRLEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ ...String:
DIVMTQSPAT LSVSPGERAT LSCRASESVS SDLAWYQQKP GQAPRLLIYG ASTRATGVPA RFSGSGSGAE FTLTISSLQS EDFAVYYCQ QYNNWPPRYT FGQGTRLEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRG

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Macromolecule #4: 17b Fab Heavy Chain

MacromoleculeName: 17b Fab Heavy Chain / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.748771 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGAE VKKPGSSVKV SCKASGDTFI RYSFTWVRQA PGQGLEWMGR IITILDVAHY APHLQGRVTI TADKSTSTVY LELRNLRSD DTAVYFCAGV YEGEADEGEY DNNGFLKHWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD Y FPEPVTVS ...String:
EVQLVESGAE VKKPGSSVKV SCKASGDTFI RYSFTWVRQA PGQGLEWMGR IITILDVAHY APHLQGRVTI TADKSTSTVY LELRNLRSD DTAVYFCAGV YEGEADEGEY DNNGFLKHWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD Y FPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKHHHHH H

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Macromolecule #5: M48U1

MacromoleculeName: M48U1 / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Leiurus quinquestriatus hebraeus (scorpion)
Molecular weightTheoretical: 3.056804 KDa
SequenceString:
(MPT)NLHFCQLRC KSLGLLGRCA (DPR)T(U2X)CACV(NH2)

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 8 / 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

Concentration1.4 mg/mL
BufferpH: 8
Component:
ConcentrationNameFormula
20.0 mMTris
100.0 mMSodium chlorideNaCl
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295.5 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was monodisperse

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 2688 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 263981
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

Initial model(PDB ID:

6u0l

,

4jzz

,

2nxy

)
Output model

PDB-7lok:
Structure of CD4 mimetic M48U1 in complex with BG505 SOSIP.664 HIV-1 Env trimer and 17b Fab

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