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- PDB-8tr3: Cryo-EM structure of HmAb64 scFv in complex with CNE40 SOSIP trimer -

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Basic information

Entry
Database: PDB / ID: 8tr3
TitleCryo-EM structure of HmAb64 scFv in complex with CNE40 SOSIP trimer
Components
  • CNE40 SOSIP Envelope glycoprotein gp120
  • CNE40 SOSIP Transmembrane protein gp41
  • HmAb64 Fv heavy chain
  • HmAb64 Fv light chain
KeywordsIMMUNE SYSTEM/VIRAL PROTEIN / HIV / Env / glycoprotein / mAb / IMMUNE SYSTEM / IMMUNE SYSTEM-VIRAL PROTEIN 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 / 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 / host cell plasma membrane / structural molecule activity / 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
Similarity search - Domain/homology
Envelope glycoprotein gp160
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.74 Å
AuthorsChan, K.-W. / Kong, X.P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Nat Commun / Year: 2024
Title: Human CD4-binding site antibody elicited by polyvalent DNA prime-protein boost vaccine neutralizes cross-clade tier-2-HIV strains.
Authors: Shixia Wang / Kun-Wei Chan / Danlan Wei / Xiuwen Ma / Shuying Liu / Guangnan Hu / Saeyoung Park / Ruimin Pan / Ying Gu / Alexandra F Nazzari / Adam S Olia / Kai Xu / Bob C Lin / Mark K ...Authors: Shixia Wang / Kun-Wei Chan / Danlan Wei / Xiuwen Ma / Shuying Liu / Guangnan Hu / Saeyoung Park / Ruimin Pan / Ying Gu / Alexandra F Nazzari / Adam S Olia / Kai Xu / Bob C Lin / Mark K Louder / Krisha McKee / Nicole A Doria-Rose / David Montefiori / Michael S Seaman / Tongqing Zhou / Peter D Kwong / James Arthos / Xiang-Peng Kong / Shan Lu /
Abstract: The vaccine elicitation of HIV tier-2-neutralization antibodies has been a challenge. Here, we report the isolation and characterization of a CD4-binding site (CD4bs) specific monoclonal antibody, ...The vaccine elicitation of HIV tier-2-neutralization antibodies has been a challenge. Here, we report the isolation and characterization of a CD4-binding site (CD4bs) specific monoclonal antibody, HmAb64, from a human volunteer immunized with a polyvalent DNA prime-protein boost HIV vaccine. HmAb64 is derived from heavy chain variable germline gene IGHV1-18 and light chain germline gene IGKV1-39. It has a third heavy chain complementarity-determining region (CDR H3) of 15 amino acids. On a cross-clade panel of 208 HIV-1 pseudo-virus strains, HmAb64 neutralized 20 (10%), including tier-2 strains from clades B, BC, C, and G. The cryo-EM structure of the antigen-binding fragment of HmAb64 in complex with a CNE40 SOSIP trimer revealed details of its recognition; HmAb64 uses both heavy and light CDR3s to recognize the CD4-binding loop, a critical component of the CD4bs. This study demonstrates that a gp120-based vaccine can elicit antibodies capable of tier 2-HIV neutralization.
History
DepositionAug 9, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CNE40 SOSIP Envelope glycoprotein gp120
B: CNE40 SOSIP Transmembrane protein gp41
H: HmAb64 Fv heavy chain
L: HmAb64 Fv light chain
C: CNE40 SOSIP Envelope glycoprotein gp120
D: CNE40 SOSIP Transmembrane protein gp41
I: HmAb64 Fv heavy chain
M: HmAb64 Fv light chain
E: CNE40 SOSIP Envelope glycoprotein gp120
F: CNE40 SOSIP Transmembrane protein gp41
J: HmAb64 Fv heavy chain
N: HmAb64 Fv light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)301,98345
Polymers293,46412
Non-polymers8,51933
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 6 molecules ACEBDF

#1: Protein CNE40 SOSIP Envelope glycoprotein gp120


Mass: 55018.422 Da / Num. of mol.: 3 / Mutation: CNE40 SOSIP mutations
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Production host: Homo sapiens (human) / References: UniProt: D7S2E5
#2: Protein CNE40 SOSIP Transmembrane protein gp41


Mass: 17205.479 Da / Num. of mol.: 3 / Mutation: CNE40 SOSIP mutations
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Production host: Homo sapiens (human) / References: UniProt: D7S2E5

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Antibody , 2 types, 6 molecules HIJLMN

#3: Antibody HmAb64 Fv heavy chain


Mass: 13745.402 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody HmAb64 Fv light chain


Mass: 11852.093 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Sugars , 2 types, 33 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.: 6
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: 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.: 27
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
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 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-IDSource
13D structure of HmAb64 Fv in complex with CNE40 SOSIP trimerCOMPLEX#1-#40MULTIPLE SOURCES
2HmAb64 FvCOMPLEX#3-#41RECOMBINANT
3CNE40 SOSIP trimerCOMPLEX#1-#21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Human immunodeficiency virus 111676
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in.
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Image recordingElectron dose: 56.76 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
2Leginonimage acquisition
4CTFFINDCTF correction
7UCSF ChimeraXmodel fitting
11cryoSPARCclassification
12cryoSPARC3.3.23D reconstruction
13PHENIX1.20.1-4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 3.74 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 316221 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00416731
ELECTRON MICROSCOPYf_angle_d0.67822722
ELECTRON MICROSCOPYf_dihedral_angle_d4.9572382
ELECTRON MICROSCOPYf_chiral_restr0.0452682
ELECTRON MICROSCOPYf_plane_restr0.0042820

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