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- PDB-7lo6: Structure of CD4 mimetic BNM-III-170 in complex with BG505 SOSIP.... -

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Entry
Database: PDB / ID: 7lo6
TitleStructure of CD4 mimetic BNM-III-170 in complex with BG505 SOSIP.664 HIV-1 Env trimer and 17b Fab
Components
  • 17b Fab Heavy Chain
  • 17b Fab Light Chain
  • Envelope glycoprotein BG505 SOSIP.664 gp120
  • HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / CD4m / fusion / HIV-1 / entry / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


positive regulation of plasma membrane raft polarization / positive regulation of establishment of T cell polarity / positive regulation of receptor clustering / actin filament reorganization / host cell endosome membrane / mitigation of host immune response by virus / 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 ...positive regulation of plasma membrane raft polarization / positive regulation of establishment of T cell polarity / positive regulation of receptor clustering / actin filament reorganization / host cell endosome membrane / mitigation of host immune response by virus / 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 / integral component of membrane / identical protein binding / plasma membrane
Envelope glycoprotein GP120 / Envelope glycoprotein Gp160 / Gp120 core superfamily / Human immunodeficiency virus 1, envelope glycoprotein Gp120 / Retroviral envelope protein GP41-like
Envelope glycoprotein gp160 / polysac:dglcpnacb1-4dglcpnacb1-roh: / polysac:dmanpa1-6dmanpa1-3dmanpb1-4dglcpnacb1-4dglcpnacb1-roh: / polysac:dmanpa1-2dmanpa1-3[dmanpa1-6]dmanpb1-4dglcpnacb1-4dglcpnacb1-roh: / polysac:dmanpa1-2dmanpa1-3[dmanpa1-3dmanpa1-6]dmanpb1-4dglcpnacb1-4dglcpnacb1-roh:
Biological speciesHuman immunodeficiency virus 1
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsJette, C.A. / Bjorkman, P.J.
Funding support United States, 2items
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.
Validation Report
SummaryFull reportAbout validation report
History
DepositionFeb 9, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release

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Assembly

Deposited unit
A: Envelope glycoprotein BG505 SOSIP.664 gp120
B: HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41
C: Envelope glycoprotein BG505 SOSIP.664 gp120
D: HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41
E: Envelope glycoprotein BG505 SOSIP.664 gp120
F: HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41
G: 17b Fab Light Chain
H: 17b Fab Heavy Chain
I: 17b Fab Light Chain
J: 17b Fab Heavy Chain
K: 17b Fab Light Chain
L: 17b Fab Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)373,98152
Polymers360,47812
Non-polymers13,50340
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area44490 Å2
ΔGint-37 kcal/mol
Surface area105740 Å2

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Components

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Protein , 2 types, 6 molecules ACEBDF

#1: Protein Envelope glycoprotein BG505 SOSIP.664 gp120 / Env polyprotein


Mass: 53864.086 Da / Num. of mol.: 3 / Mutation: BG505 SOSIP.664
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q2N0S6
#2: Protein HIV-1 Envelope Glycoprotein BG505 SOSIP.664 gp41


Mass: 17146.482 Da / Num. of mol.: 3 / Mutation: BG505 SOSIP.664
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q2N0S6

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Antibody , 2 types, 6 molecules GIKHJL

#3: Antibody 17b Fab Light Chain


Mass: 23399.898 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#4: Antibody 17b Fab Heavy Chain


Mass: 25748.771 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)

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Sugars , 5 types, 37 molecules

#5: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_d6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_c6-f1_d2-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#8: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-3DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3/a4-b1_b4-c1_c3-d1_c6-f1_d2-e1_f3-g1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#9: Sugar...
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 27
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 1 types, 3 molecules

#10: Chemical ChemComp-5VG / ~{N}'-[(1~{R},2~{R})-2-(carbamimidamidomethyl)-5-(methylaminomethyl)-2,3-dihydro-1~{H}-inden-1-yl]-~{N}-(4-chloranyl-3-fluoranyl-phenyl)ethanediamide


Mass: 446.906 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H24ClFN6O2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSourceDetails
1Complex of BG505 SOSIP.664 Env with CD4 mimetic BNM-III-170 and 17b FabCOMPLEX#1-#40MULTIPLE SOURCES
217b FabCOMPLEX#3-#41RECOMBINANTFinal reconstruction masked out the constant domain so only coordinates for the variable domain were modeled, but full Fab was used to assemble complex.
3BG505 SOSIP.664 HIV-1 Env trimerCOMPLEX#1-#21RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.480 MDaNO
21NO
31NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-IDStrain
32Homo sapiens (human)9606
43Human immunodeficiency virus 111676BG505
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
22Homo sapiens (human)9606HEK293
33Homo sapiens (human)9606HEK293
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTris1
2100 mMsodium chlorideNaClSodium chloride1
SpecimenConc.: 1.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was monodisperse
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295.5 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
7UCSF Chimeramodel fitting
8PHENIX1.18model fitting
10PHENIX1.18model refinement
14RELION33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 662861 / Symmetry type: POINT
Atomic model building
IDPDB-ID3D fitting-ID
16U0L1
25F4P1
32NXY1
RefinementHighest resolution: 3.9 Å
Refine LS restraints
Refinement-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01118390
ELECTRON MICROSCOPYf_angle_d0.88324980
ELECTRON MICROSCOPYf_dihedral_angle_d16.2732751
ELECTRON MICROSCOPYf_chiral_restr0.0552956
ELECTRON MICROSCOPYf_plane_restr0.0053102

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