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- PDB-6cdm: Structure of vaccine-elicited HIV-1 neutralizing antibody vFP7.04... -

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Basic information

Entry
Database: PDB / ID: 6cdm
TitleStructure of vaccine-elicited HIV-1 neutralizing antibody vFP7.04 in complex with HIV-1 fusion peptide residue 512-519
Components
  • HIV fusion peptide (512-519)
  • vFP7.04 heavy chain
  • vFP7.04 light chain
KeywordsIMMUNE SYSTEM / Neutralizing / antibody / fusion peptide / complex
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 / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Envelope glycoprotein gp160
Similarity search - Component
Biological speciesMus musculus (house mouse)
Human immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.408 Å
AuthorsXu, K. / Liu, K. / Kwong, P.D.
CitationJournal: Nat Med / Year: 2018
Title: Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1.
Authors: Kai Xu / Priyamvada Acharya / Rui Kong / Cheng Cheng / Gwo-Yu Chuang / Kevin Liu / Mark K Louder / Sijy O'Dell / Reda Rawi / Mallika Sastry / Chen-Hsiang Shen / Baoshan Zhang / Tongqing Zhou ...Authors: Kai Xu / Priyamvada Acharya / Rui Kong / Cheng Cheng / Gwo-Yu Chuang / Kevin Liu / Mark K Louder / Sijy O'Dell / Reda Rawi / Mallika Sastry / Chen-Hsiang Shen / Baoshan Zhang / Tongqing Zhou / Mangaiarkarasi Asokan / Robert T Bailer / Michael Chambers / Xuejun Chen / Chang W Choi / Venkata P Dandey / Nicole A Doria-Rose / Aliaksandr Druz / Edward T Eng / S Katie Farney / Kathryn E Foulds / Hui Geng / Ivelin S Georgiev / Jason Gorman / Kurt R Hill / Alexander J Jafari / Young D Kwon / Yen-Ting Lai / Thomas Lemmin / Krisha McKee / Tiffany Y Ohr / Li Ou / Dongjun Peng / Ariana P Rowshan / Zizhang Sheng / John-Paul Todd / Yaroslav Tsybovsky / Elise G Viox / Yiran Wang / Hui Wei / Yongping Yang / Amy F Zhou / Rui Chen / Lu Yang / Diana G Scorpio / Adrian B McDermott / Lawrence Shapiro / Bridget Carragher / Clinton S Potter / John R Mascola / Peter D Kwong /
Abstract: A central goal of HIV-1 vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N- ...A central goal of HIV-1 vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryoelectron microscopy structures of these antibodies revealed fusion peptide conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses, suggesting translatability. The N terminus of the HIV-1 fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.
History
DepositionFeb 8, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 20, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: vFP7.04 heavy chain
B: vFP7.04 light chain
C: HIV fusion peptide (512-519)
D: vFP7.04 heavy chain
E: vFP7.04 light chain
F: HIV fusion peptide (512-519)


Theoretical massNumber of molelcules
Total (without water)96,9696
Polymers96,9696
Non-polymers00
Water6,323351
1
A: vFP7.04 heavy chain
B: vFP7.04 light chain
C: HIV fusion peptide (512-519)


Theoretical massNumber of molelcules
Total (without water)48,4843
Polymers48,4843
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4550 Å2
ΔGint-36 kcal/mol
Surface area19490 Å2
MethodPISA
2
D: vFP7.04 heavy chain
E: vFP7.04 light chain
F: HIV fusion peptide (512-519)


Theoretical massNumber of molelcules
Total (without water)48,4843
Polymers48,4843
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4570 Å2
ΔGint-36 kcal/mol
Surface area19430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.565, 61.034, 88.654
Angle α, β, γ (deg.)90.000, 91.890, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain D
12chain C
22chain F
13chain B
23chain E

NCS domain segments:

Component-ID: 1

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLNGLNPROPROchain AAA1 - 2131 - 218
21GLNGLNPROPROchain DDD1 - 2131 - 218
12ALAALAALAALAchain CCC512 - 5171 - 6
22ALAALAALAALAchain FFF512 - 5171 - 6
13GLYGLYGLUGLUchain BBB1 - 2131 - 218
23GLYGLYGLUGLUchain EEE1 - 2131 - 218

NCS ensembles :
ID
1
2
3

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Components

#1: Antibody vFP7.04 heavy chain


Mass: 23720.730 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#2: Antibody vFP7.04 light chain


Mass: 24030.855 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Protein/peptide HIV fusion peptide (512-519)


Mass: 732.868 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Human immunodeficiency virus 1 / References: UniProt: Q2N0S5*PLUS
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 351 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.22 Å3/Da / Density % sol: 44.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M MES pH 6.0, 30% PEG 6000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Nov 17, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 33013 / % possible obs: 99.6 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.127 / Rpim(I) all: 0.079 / Rrim(I) all: 0.15 / Χ2: 0.767 / Net I/σ(I): 4.9 / Num. measured all: 113946
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.4-2.442.80.41215670.7980.2790.50.5995.7
2.44-2.492.90.37316140.840.2490.450.58897.6
2.49-2.532.90.35616280.8390.240.4320.5798.7
2.53-2.5930.34916100.8550.2330.4210.61199.5
2.59-2.643.10.34116640.8730.2260.4110.58299.8
2.64-2.73.30.34216270.8490.2250.4110.66100
2.7-2.773.40.3116610.8840.2010.370.657100
2.77-2.853.50.29716570.9170.1870.3520.706100
2.85-2.933.60.25716480.930.1590.3030.696100
2.93-3.023.70.25216380.9350.1540.2960.771100
3.02-3.133.70.22416420.9450.1350.2620.786100
3.13-3.263.70.18716480.9650.1140.220.823100
3.26-3.413.70.15416520.9750.0930.180.861100
3.41-3.583.70.12716760.9780.0770.1490.866100
3.58-3.813.70.10316500.9840.0620.120.84100
3.81-4.13.70.0916630.9870.0540.1050.959100
4.1-4.523.70.0716610.9930.0420.0820.973100
4.52-5.173.70.06216810.9950.0380.0720.864100
5.17-6.513.70.06516830.9940.040.0760.724100
6.51-503.50.05417430.9960.0340.0640.901100

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BKY

3bky


Resolution: 2.408→48.417 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 21.37
RfactorNum. reflection% reflection
Rfree0.2223 1565 4.74 %
Rwork0.1835 --
obs0.1853 32997 99.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 76.42 Å2 / Biso mean: 27.5734 Å2 / Biso min: 12.96 Å2
Refinement stepCycle: final / Resolution: 2.408→48.417 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6724 0 0 351 7075
Biso mean---31.92 -
Num. residues----884
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0056888
X-RAY DIFFRACTIONf_angle_d0.9119372
X-RAY DIFFRACTIONf_chiral_restr0.0541066
X-RAY DIFFRACTIONf_plane_restr0.0051184
X-RAY DIFFRACTIONf_dihedral_angle_d8.7244076
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1996X-RAY DIFFRACTION7.933TORSIONAL
12D1996X-RAY DIFFRACTION7.933TORSIONAL
21C36X-RAY DIFFRACTION7.933TORSIONAL
22F36X-RAY DIFFRACTION7.933TORSIONAL
31B1993X-RAY DIFFRACTION7.933TORSIONAL
32E1993X-RAY DIFFRACTION7.933TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4077-2.48540.28161230.22082662278593
2.4854-2.57420.25691660.20482813297999
2.5742-2.67730.26681290.204128682997100
2.6773-2.79910.25271320.202528562988100
2.7991-2.94670.26421360.193828953031100
2.9467-3.13130.23281650.189628162981100
3.1313-3.3730.20441510.172828773028100
3.373-3.71230.20471350.162528663001100
3.7123-4.24920.22551290.165528923021100
4.2492-5.35250.15961340.164129283062100
5.3525-48.4270.23061650.209629593124100

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