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Yorodumi- EMDB-26157: Cryo-EM structure of BG505 SOSIP HIV-1 Env trimer in complex with... -
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-Basic information
Entry | Database: EMDB / ID: EMD-26157 | |||||||||
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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 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | HIV / Env / Broadly Neutralizing / Darpin / CD4 / VIRAL PROTEIN | |||||||||
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 | single particle reconstruction / cryo EM / Resolution: 3.87 Å | |||||||||
Authors | Cerutti G / Gorman J | |||||||||
Funding support | United States, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_26157.map.gz | 117.1 MB | EMDB map data format | |
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Header (meta data) | emd-26157-v30.xml emd-26157.xml | 16.9 KB 16.9 KB | Display Display | EMDB header |
Images | emd_26157.png | 123.2 KB | ||
Others | emd_26157_additional_1.map.gz | 118 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-26157 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-26157 | HTTPS FTP |
-Validation report
Summary document | emd_26157_validation.pdf.gz | 480.5 KB | Display | EMDB validaton report |
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Full document | emd_26157_full_validation.pdf.gz | 480 KB | Display | |
Data in XML | emd_26157_validation.xml.gz | 6.6 KB | Display | |
Data in CIF | emd_26157_validation.cif.gz | 7.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-26157 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-26157 | HTTPS FTP |
-Related structure data
Related structure data | 7txdMC 7z7cC 8aedC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_26157.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: Local refinement map
File | emd_26157_additional_1.map | ||||||||||||
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Annotation | Local refinement map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : BG505 SOSIP HIV-1 Env trimer in complex with CD4 receptor (D1D2) ...
Entire | Name: BG505 SOSIP HIV-1 Env trimer in complex with CD4 receptor (D1D2) and broadly neutralizing darpin bnD.9 |
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Components |
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-Supramolecule #1: BG505 SOSIP HIV-1 Env trimer in complex with CD4 receptor (D1D2) ...
Supramolecule | Name: BG505 SOSIP HIV-1 Env trimer in complex with CD4 receptor (D1D2) and broadly neutralizing darpin bnD.9 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: Human immunodeficiency virus 1 |
-Macromolecule #1: Envelope glycoprotein gp120
Macromolecule | Name: Envelope glycoprotein gp120 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Human immunodeficiency virus 1 |
Molecular weight | Theoretical: 54.064277 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHTDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT ...String: AENLWVTVYY GVPVWKDAET TLFCASDAKA YETEKHNVWA THACVPTDPN PQEIHLENVT EEFNMWKNNM VEQMHTDIIS LWDQSLKPC VKLTPLCVTL QCTNVTNNIT DDMRGELKNC SFNMTTELRD KKQKVYSLFY RLDVVQINEN QGNRSNNSNK E YRLINCNT SAITQACPKV SFEPIPIHYC APAGFAILKC KDKKFNGTGP CPSVSTVQCT HGIKPVVSTQ LLLNGSLAEE EV MIRSENI TNNAKNILVQ FNTPVQINCT RPNNNTRKSI RIGPGQAFYA TGDIIGDIRQ AHCNVSKATW NETLGKVVKQ LRK HFGNNT IIRFANSSGG DLEVTTHSFN CGGEFFYCNT SGLFNSTWIS NTSVQGSNST GSNDSITLPC RIKQIINMWQ RIGQ AMYAP PIQGVIRCVS NITGLILTRD GGSTNSTTET FRPGGGDMRD NWRSELYKYK VVKIEPLGVA PTRCKRRVVG RRRRR R UniProtKB: Envelope glycoprotein gp160 |
-Macromolecule #2: Envelope glycoprotein gp41
Macromolecule | Name: Envelope glycoprotein gp41 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Human immunodeficiency virus 1 |
Molecular weight | Theoretical: 17.146482 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: AVGIGAVFLG FLGAAGSTMG AASMTLTVQA RNLLSGIVQQ QSNLLRAPEA QQHLLKLTVW GIKQLQARVL AVERYLRDQQ LLGIWGCSG KLICCTNVPW NSSWSNRNLS EIWDNMTWLQ WDKEISNYTQ IIYGLLEESQ NQQEKNEQDL LALD UniProtKB: Envelope glycoprotein gp160 |
-Macromolecule #3: T-cell surface glycoprotein CD4
Macromolecule | Name: T-cell surface glycoprotein CD4 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 20.50326 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: KKVVLGKKGD TVELTCTASQ KKSIQFHWKN SNQIKILGNQ GSFLTKGPSK LNDRADSRRS LWDQGNFPLI IKNLKIEDSD TYICEVEDQ KEEVQLLVFG LTANSDTHLL QGQSLTLTLE SPPGSSPSVQ CRSPRGKNIQ GGKTLSVSQL ELQDSGTWTC T VLQNQKKV EFKIDIVVLA FQKASNT UniProtKB: T-cell surface glycoprotein CD4 |
-Macromolecule #4: Broadly neutralizing darpin bnd.9
Macromolecule | Name: Broadly neutralizing darpin bnd.9 / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 21.214891 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: GLNDIFEAQK IEWHEGSGGS DLGKKLLEAA YYGQLDEVRI LMANGADVNA VDVHGITPLH LAAYFGHLEI VEVLLKTGAD VNARDNRGI TPLHLAAAMG HLEIVEVLLK AGADVNAFDE AGDTPLHLAA LKGHLEIVEV LLKHGADVNA QDKFGKTAFD I SIDNGNED ...String: GLNDIFEAQK IEWHEGSGGS DLGKKLLEAA YYGQLDEVRI LMANGADVNA VDVHGITPLH LAAYFGHLEI VEVLLKTGAD VNARDNRGI TPLHLAAAMG HLEIVEVLLK AGADVNAFDE AGDTPLHLAA LKGHLEIVEV LLKHGADVNA QDKFGKTAFD I SIDNGNED IAEVLQKAAK LNLEVLFQGP HHHHHHHH |
-Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 30 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 42.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.87 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 115325 |
Initial angle assignment | Type: OTHER / Software - Name: cryoSPARC |
Final angle assignment | Type: OTHER / Software - Name: cryoSPARC |