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- PDB-6nc2: AMC011 v4.2 SOSIP Env trimer in complex with fusion peptide targe... -

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Basic information

Entry
Database: PDB / ID: 6nc2
TitleAMC011 v4.2 SOSIP Env trimer in complex with fusion peptide targeting antibody ACS202 fragment antigen binding
Components
  • (AMC011 v4.2 SOSIP ...) x 2
  • (Monoclonal antibody ACS202 fragment antigen binding ...) x 2
KeywordsIMMUNE SYSTEM / HIV-1 Env / SOSIP / trimer / broadly neutralizing antibody / fusion peptide / VIRAL PROTEIN
Function / homologyRetroviral envelope protein / Retroviral envelope protein GP41-like / membrane => GO:0016020 / viral envelope / host cell plasma membrane / virion membrane / structural molecule activity / plasma membrane / Env polyprotein
Function and homology information
Biological speciesHuman immunodeficiency virus 1
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.2 Å
AuthorsCottrell, C.A. / Ozorowski, G. / Yuan, M. / Copps, J. / Wilson, I.A. / Ward, A.B.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01 AI110657 United States
Bill & Melinda Gates FoundationOPP1115782 United States
Bill & Melinda Gates FoundationOPP1084519 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)F31 Al131873 United States
Other private109718-63-RKNT United States
CitationJournal: Cell Host Microbe / Year: 2019
Title: Conformational Plasticity in the HIV-1 Fusion Peptide Facilitates Recognition by Broadly Neutralizing Antibodies.
Authors: Meng Yuan / Christopher A Cottrell / Gabriel Ozorowski / Marit J van Gils / Sonu Kumar / Nicholas C Wu / Anita Sarkar / Jonathan L Torres / Natalia de Val / Jeffrey Copps / John P Moore / ...Authors: Meng Yuan / Christopher A Cottrell / Gabriel Ozorowski / Marit J van Gils / Sonu Kumar / Nicholas C Wu / Anita Sarkar / Jonathan L Torres / Natalia de Val / Jeffrey Copps / John P Moore / Rogier W Sanders / Andrew B Ward / Ian A Wilson /
Abstract: The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as ...The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a "β strand" interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.
History
DepositionDec 10, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.pdbx_database_id_PubMed ..._citation.page_first / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / em_entity_assembly / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _em_entity_assembly.entity_id_list / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: AMC011 v4.2 SOSIP gp120
B: AMC011 v4.2 SOSIP gp41
H: Monoclonal antibody ACS202 fragment antigen binding heavy chain
L: Monoclonal antibody ACS202 fragment antigen binding kappa chain
C: AMC011 v4.2 SOSIP gp120
I: AMC011 v4.2 SOSIP gp41
O: Monoclonal antibody ACS202 fragment antigen binding heavy chain
T: Monoclonal antibody ACS202 fragment antigen binding kappa chain
D: AMC011 v4.2 SOSIP gp120
J: AMC011 v4.2 SOSIP gp41
P: Monoclonal antibody ACS202 fragment antigen binding heavy chain
U: Monoclonal antibody ACS202 fragment antigen binding kappa chain
E: AMC011 v4.2 SOSIP gp120
K: AMC011 v4.2 SOSIP gp41
Q: Monoclonal antibody ACS202 fragment antigen binding heavy chain
V: Monoclonal antibody ACS202 fragment antigen binding kappa chain
F: AMC011 v4.2 SOSIP gp120
M: AMC011 v4.2 SOSIP gp41
R: Monoclonal antibody ACS202 fragment antigen binding heavy chain
W: Monoclonal antibody ACS202 fragment antigen binding kappa chain
G: AMC011 v4.2 SOSIP gp120
N: AMC011 v4.2 SOSIP gp41
S: Monoclonal antibody ACS202 fragment antigen binding heavy chain
X: Monoclonal antibody ACS202 fragment antigen binding kappa chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)793,57478
Polymers767,02424
Non-polymers26,55054
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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AMC011 v4.2 SOSIP ... , 2 types, 12 molecules ACDEFGBIJKMN

#1: Protein
AMC011 v4.2 SOSIP gp120


Mass: 57668.938 Da / Num. of mol.: 6 / Mutation: H66R, A316W, A501C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#2: Protein
AMC011 v4.2 SOSIP gp41


Mass: 17300.666 Da / Num. of mol.: 6 / Mutation: L543Q, I559P, Q567K, T605C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q78156*PLUS

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Antibody , 2 types, 12 molecules HOPQRSLTUVWX

#3: Antibody
Monoclonal antibody ACS202 fragment antigen binding heavy chain


Mass: 27392.023 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#4: Antibody
Monoclonal antibody ACS202 fragment antigen binding kappa chain


Mass: 25475.658 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)

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Sugars , 4 types, 54 molecules

#5: Polysaccharide
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-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: 910.823 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam 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_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#6: 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.: 6
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}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.: 6
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-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: Sugar...
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 30
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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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-IDSource
1Complex of AMC011 v4.2 SOSIP trimer and ACS202 fragment antigen bindingCOMPLEX#1-#40MULTIPLE SOURCES
2HIV-1 Env AMC011 v4.2 SOSIP gp120COMPLEX#11RECOMBINANT
3HIV-1 Env AMC011 v4.2 SOSIP gp41COMPLEX#21RECOMBINANT
4VRC34.01COMPLEX#3-#41RECOMBINANT
Molecular weightValue: 0.57 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Human immunodeficiency virus 111676
23Human immunodeficiency virus 111676
34Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Homo sapiens (human)9606
Buffer solutionpH: 7.4
Details: Detergent (DDM) added immediately prior to grid preparation
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTris1
2150 mMSodium chlorideNaClSodium chloride1
30.06 mMn-dodecyl beta-D-maltoside1
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: SEC purified sample after overnight incubation of molar excess Fab to trimer
Specimen supportDetails: Gatan Solarus 950 Plasma system / Grid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat-2/2 4C
VitrificationInstrument: HOMEMADE PLUNGER / Cryogen name: ETHANE

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 29000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1300 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 10 sec. / Electron dose: 92 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 1641
Image scansSampling size: 5 µm / Width: 3710 / Height: 3838 / Movie frames/image: 50

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Processing

EM software
IDNameVersionCategory
1DoG Pickerparticle selection
2Leginonimage acquisition
4Gctf1.06CTF correction
9RELION2.1initial Euler assignment
10RELION2.1final Euler assignment
11RELION2.1classification
12RELION2.13D reconstruction
13Rosetta3.1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: D3 (2x3 fold dihedral)
3D reconstructionResolution: 5.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 49878 / Symmetry type: POINT
Atomic model buildingSpace: REAL

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