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Yorodumi- PDB-7txd: Cryo-EM structure of BG505 SOSIP HIV-1 Env trimer in complex with... -
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-Basic information
Entry | Database: PDB / ID: 7txd | ||||||
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Title | Cryo-EM structure of BG505 SOSIP HIV-1 Env trimer in complex with CD4 receptor (D1D2) and broadly neutralizing darpin bnD.9 | ||||||
Components |
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Keywords | VIRAL PROTEIN / HIV / Env / Broadly Neutralizing / Darpin / CD4 | ||||||
Function / homology | Function and homology information helper T cell enhancement of adaptive immune response / interleukin-16 binding / interleukin-16 receptor activity / maintenance of protein location in cell / T cell selection / MHC class II protein binding / cellular response to granulocyte macrophage colony-stimulating factor stimulus / interleukin-15-mediated signaling pathway / positive regulation of monocyte differentiation / Nef Mediated CD4 Down-regulation ...helper T cell enhancement of adaptive immune response / interleukin-16 binding / interleukin-16 receptor activity / maintenance of protein location in cell / T cell selection / MHC class II protein binding / cellular response to granulocyte macrophage colony-stimulating factor stimulus / interleukin-15-mediated signaling pathway / positive regulation of monocyte differentiation / Nef Mediated CD4 Down-regulation / Alpha-defensins / positive regulation of kinase activity / regulation of T cell activation / T cell receptor complex / extracellular matrix structural constituent / Other interleukin signaling / enzyme-linked receptor protein signaling pathway / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / regulation of calcium ion transport / macrophage differentiation / Generation of second messenger molecules / T cell differentiation / PD-1 signaling / positive regulation of protein kinase activity / Binding and entry of HIV virion / coreceptor activity / positive regulation of calcium-mediated signaling / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of establishment of T cell polarity / T cell activation / positive regulation of interleukin-2 production / protein tyrosine kinase binding / host cell endosome membrane / Vpu mediated degradation of CD4 / calcium-mediated signaling / clathrin-coated endocytic vesicle membrane / transmembrane signaling receptor activity / positive regulation of peptidyl-tyrosine phosphorylation / Downstream TCR signaling / Cargo recognition for clathrin-mediated endocytosis / positive regulation of T cell activation / MHC class II protein complex binding / Clathrin-mediated endocytosis / virus receptor activity / signaling receptor activity / clathrin-dependent endocytosis of virus by host cell / positive regulation of canonical NF-kappaB signal transduction / defense response to Gram-negative bacterium / adaptive immune response / positive regulation of MAPK cascade / positive regulation of viral entry into host cell / positive regulation of ERK1 and ERK2 cascade / cell surface receptor signaling pathway / early endosome / viral protein processing / cell adhesion / positive regulation of protein phosphorylation / immune response / membrane raft / endoplasmic reticulum lumen / external side of plasma membrane / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / lipid binding / viral envelope / virion attachment to host cell / endoplasmic reticulum membrane / protein kinase binding / host cell plasma membrane / structural molecule activity / positive regulation of DNA-templated transcription / virion membrane / enzyme binding / signal transduction / protein homodimerization activity / zinc ion binding / identical protein binding / plasma membrane Similarity search - Function | ||||||
Biological species | Human immunodeficiency virus 1 Homo sapiens (human) synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.87 Å | ||||||
Authors | Cerutti, G. / Gorman, J. / Kwong, P.D. / Shapiro, L. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Struct Mol Biol / Year: 2023 Title: Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization. Authors: Matthias Glögl / Nikolas Friedrich / Gabriele Cerutti / Thomas Lemmin / Young D Kwon / Jason Gorman / Liridona Maliqi / Peer R E Mittl / Maria C Hesselman / Daniel Schmidt / Jacqueline ...Authors: Matthias Glögl / Nikolas Friedrich / Gabriele Cerutti / Thomas Lemmin / Young D Kwon / Jason Gorman / Liridona Maliqi / Peer R E Mittl / Maria C Hesselman / Daniel Schmidt / Jacqueline Weber / Caio Foulkes / Adam S Dingens / Tatsiana Bylund / Adam S Olia / Raffaello Verardi / Thomas Reinberg / Nicolas S Baumann / Peter Rusert / Birgit Dreier / Lawrence Shapiro / Peter D Kwong / Andreas Plückthun / Alexandra Trkola / Abstract: The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows ...The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic α-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'αV3C'. The bnD contact surface on αV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of αV3C, highlighting the potential of αV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7txd.cif.gz | 460.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7txd.ent.gz | 383.7 KB | Display | PDB format |
PDBx/mmJSON format | 7txd.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7txd_validation.pdf.gz | 2.3 MB | Display | wwPDB validaton report |
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Full document | 7txd_full_validation.pdf.gz | 2.3 MB | Display | |
Data in XML | 7txd_validation.xml.gz | 71.8 KB | Display | |
Data in CIF | 7txd_validation.cif.gz | 106.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/tx/7txd ftp://data.pdbj.org/pub/pdb/validation_reports/tx/7txd | HTTPS FTP |
-Related structure data
Related structure data | 26157MC 7z7cC 8aedC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Envelope glycoprotein ... , 2 types, 6 molecules ACEBDF
#1: Protein | Mass: 54064.277 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Production host: Homo sapiens (human) / References: UniProt: Q2N0S6 #2: Protein | Mass: 17146.482 Da / Num. of mol.: 3 / Fragment: UNP residues 509-661 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: env / Production host: Homo sapiens (human) / References: UniProt: Q2N0S6 |
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-Protein , 2 types, 6 molecules GHIJKL
#3: Protein | Mass: 20503.260 Da / Num. of mol.: 3 / Fragment: D1-D2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CD4 / Production host: Homo sapiens (human) / References: UniProt: P01730 #4: Protein | Mass: 21214.891 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: Homo sapiens (human) |
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-Sugars , 5 types, 52 molecules
#5: Polysaccharide | Source method: isolated from a genetically manipulated source #6: Polysaccharide | beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #7: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #8: 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 | Source method: isolated from a genetically manipulated source #9: Sugar | ChemComp-NAG / |
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-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: BG505 SOSIP HIV-1 Env trimer in complex with CD4 receptor (D1D2) and broadly neutralizing darpin bnD.9 Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Human immunodeficiency virus 1 |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 42 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.19.2_4158: / Classification: refinement | ||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.87 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 115325 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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