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- PDB-8sw4: BG505 GT1.1 SOSIP in complex with NHP Fabs 21N13, 21M20 and RM20A3 -

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Basic information

Entry
Database: PDB / ID: 8sw4
TitleBG505 GT1.1 SOSIP in complex with NHP Fabs 21N13, 21M20 and RM20A3
Components
  • 21M20 heavy chain variable region
  • 21M20 light chain variable region
  • 21N13 heavy chain variable region
  • 21N13 light chain variable region
  • BG505 GT1.1 SOSIP gp120
  • Envelope glycoprotein gp41
  • RM20A3 heavy chain variable region
  • RM20A3 light chain variable region
KeywordsVIRAL PROTEIN / germline targeting / HIV-1 Env / neutralizing antibody / non-human primate antibody / CD4 binding site / fusion peptide
Function / homology
Function and homology information


positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / 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 / virion attachment to host cell / host cell plasma membrane ...positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / 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 / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / identical protein binding / 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 speciesMacaca (macaques)
Human immunodeficiency virus 1
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.85 Å
AuthorsOzorowski, G. / Torres, J.L. / Zhang, S. / Ward, A.B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01 AI110657 United States
CitationJournal: Sci Immunol / Year: 2024
Title: Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site.
Authors: Tom G Caniels / Max Medina-Ramìrez / Shiyu Zhang / Sven Kratochvil / Yuejiao Xian / Ja-Hyun Koo / Ronald Derking / Jakob Samsel / Jelle van Schooten / Simone Pecetta / Edward Lamperti / ...Authors: Tom G Caniels / Max Medina-Ramìrez / Shiyu Zhang / Sven Kratochvil / Yuejiao Xian / Ja-Hyun Koo / Ronald Derking / Jakob Samsel / Jelle van Schooten / Simone Pecetta / Edward Lamperti / Meng Yuan / María Ríos Carrasco / Iván Del Moral Sánchez / Joel D Allen / Joey H Bouhuijs / Anila Yasmeen / Thomas J Ketas / Jonne L Snitselaar / Tom P L Bijl / Isabel Cuella Martin / Jonathan L Torres / Albert Cupo / Lisa Shirreff / Kenneth Rogers / Rosemarie D Mason / Mario Roederer / Kelli M Greene / Hongmei Gao / Catarina Mendes Silva / Isabel J L Baken / Ming Tian / Frederick W Alt / Bali Pulendran / Michael S Seaman / Max Crispin / Marit J van Gils / David C Montefiori / Adrian B McDermott / François J Villinger / Richard A Koup / John P Moore / Per Johan Klasse / Gabriel Ozorowski / Facundo D Batista / Ian A Wilson / Andrew B Ward / Rogier W Sanders /
Abstract: Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), ...Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)-specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.
History
DepositionMay 17, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2024Provider: repository / Type: Initial release
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Revision 1.1Sep 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: 21M20 heavy chain variable region
L: 21M20 light chain variable region
A: BG505 GT1.1 SOSIP gp120
B: Envelope glycoprotein gp41
E: RM20A3 heavy chain variable region
F: RM20A3 light chain variable region
C: BG505 GT1.1 SOSIP gp120
G: Envelope glycoprotein gp41
J: RM20A3 heavy chain variable region
M: RM20A3 light chain variable region
D: BG505 GT1.1 SOSIP gp120
I: Envelope glycoprotein gp41
K: RM20A3 heavy chain variable region
N: RM20A3 light chain variable region
O: 21N13 heavy chain variable region
P: 21N13 light chain variable region
Q: 21N13 heavy chain variable region
R: 21N13 light chain variable region
S: 21N13 heavy chain variable region
T: 21N13 light chain variable region
hetero molecules


Theoretical massNumber of molelcules
Total (without water)412,57457
Polymers402,60320
Non-polymers9,97037
Water00
1


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

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Components

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Protein , 3 types, 7 molecules HACDBGI

#1: Protein 21M20 heavy chain variable region


Mass: 13737.351 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca (macaques) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#3: Protein BG505 GT1.1 SOSIP gp120


Mass: 57275.480 Da / Num. of mol.: 3
Mutation: E64K, K169R, Y173H, S174A, R178K, V181I, Q183P, G188N, N189T, E190S, S199A, E275K, N276D, T278R, A316W, N386D, N462D, G471S, 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)
#4: Protein Envelope glycoprotein gp41 / Env polyprotein


Mass: 17146.482 Da / Num. of mol.: 3 / Fragment: UNP residues 509-661 / Mutation: I559P, T605C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Cell line: HEK293F / Gene: env / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q2N0S6

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Antibody , 5 types, 13 molecules LEJKFMNOQSPRT

#2: Antibody 21M20 light chain variable region


Mass: 11358.563 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca (macaques) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#5: Antibody RM20A3 heavy chain variable region


Mass: 13424.034 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca (macaques) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#6: Antibody RM20A3 light chain variable region


Mass: 11755.821 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca (macaques) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#7: Antibody 21N13 heavy chain variable region


Mass: 14476.926 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca (macaques) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#8: Antibody 21N13 light chain variable region


Mass: 11757.068 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Macaca (macaques) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)

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Sugars , 3 types, 37 molecules

#9: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...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: 748.682 Da / Num. of mol.: 3 / Source method: obtained synthetically
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#10: 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.: 1
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
#11: 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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 33 / Source method: obtained synthetically / 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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Details

Has ligand of interestN
Has protein modificationY

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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

ComponentName: BG505 GT1.1 SOSIP in complex with 21N13 Fab, 21M20 Fab and RM20A3 Fab
Type: COMPLEX / Entity ID: #1-#8 / Source: RECOMBINANT
Molecular weightValue: 0.77 MDa / Experimental value: NO
Source (natural)Organism: Macaca (macaques)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4 / Details: Detergent added shortly before freezing
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTris1
2150 mMSodium chlorideNaCl1
30.06 mMn-Dodecyl-B-D-Maltopyranoside1
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 190000 X / Nominal defocus max: 1500 nm / Nominal defocus min: 700 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 48.5 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategoryDetails
1cryoSPARC4particle selectionBlob picker
2cryoSPARC4particle selectionTemplate picker
3EPUimage acquisition
5cryoSPARC4CTF correctionPatch CTF
9PHENIXmodel refinement
14cryoSPARC43D reconstructionNon-uniform refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 242098 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00726890
ELECTRON MICROSCOPYf_angle_d1.14236494
ELECTRON MICROSCOPYf_dihedral_angle_d12.8699745
ELECTRON MICROSCOPYf_chiral_restr0.0694164
ELECTRON MICROSCOPYf_plane_restr0.0064606

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