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Yorodumi- EMDB-22049: Asymmetric reconstruction of CD4- and 17b-bound B41 HIV-1 Env SOS... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-22049 | ||||||||||||
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Title | Asymmetric reconstruction of CD4- and 17b-bound B41 HIV-1 Env SOSIP in complex with small molecule GO52 | ||||||||||||
Map data | sharpened map | ||||||||||||
Sample |
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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 / protein tyrosine kinase binding / positive regulation of establishment of T cell polarity / positive regulation of interleukin-2 production / virus-mediated perturbation of host defense response / T cell activation / host cell endosome membrane / Vpu mediated degradation of CD4 / calcium-mediated signaling / clathrin-coated endocytic vesicle membrane / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of T cell activation / positive regulation of peptidyl-tyrosine phosphorylation / transmembrane signaling receptor activity / Cargo recognition for clathrin-mediated endocytosis / Downstream TCR signaling / virus receptor activity / signaling receptor activity / MHC class II protein complex binding / Clathrin-mediated endocytosis / clathrin-dependent endocytosis of virus by host cell / positive regulation of canonical NF-kappaB signal transduction / defense response to Gram-negative bacterium / positive regulation of MAPK cascade / adaptive immune response / positive regulation of viral entry into host cell / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / viral protein processing / early endosome / cell adhesion / immune response / positive regulation of protein phosphorylation / membrane raft / fusion of virus membrane with host plasma membrane / external side of plasma membrane / endoplasmic reticulum lumen / fusion of virus membrane with host endosome membrane / viral envelope / lipid binding / endoplasmic reticulum membrane / virion attachment to host cell / protein kinase binding / host cell plasma membrane / virion membrane / structural molecule activity / positive regulation of DNA-templated transcription / 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) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.04 Å | ||||||||||||
Authors | Ozorowski G / Torres JL / Ward AB | ||||||||||||
Funding support | United States, 3 items
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Citation | Journal: Cell Rep / Year: 2020 Title: A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket near the Fusion Peptide. Authors: Gabriel Ozorowski / Jonathan L Torres / Diogo Santos-Martins / Stefano Forli / Andrew B Ward / Abstract: Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron ...Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron microscopy (cryo-EM), we identify a pocket near the base of the trimer containing a bound detergent molecule and perform in silico drug screening by using a library of drug-like and commercially available molecules. After down-selection, we solve cryo-EM structures that validate the binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrates low micromolar inhibition of the autologous virus by using a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing an additional target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains. #1: Journal: Biorxiv / Year: 2020 Title: A strain-specific inhibitor of receptor-bound HIV-1 targets a pocket near the fusion peptide and offers a template for drug design Authors: Ozorowski G / Torres JL / Santos-Martins D / Forli S / Ward AB | ||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_22049.map.gz | 85.3 MB | EMDB map data format | |
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Header (meta data) | emd-22049-v30.xml emd-22049.xml | 22.3 KB 22.3 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_22049_fsc.xml | 10.3 KB | Display | FSC data file |
Images | emd_22049.png | 188.6 KB | ||
Masks | emd_22049_msk_1.map | 91.1 MB | Mask map | |
Others | emd_22049_half_map_1.map.gz emd_22049_half_map_2.map.gz | 71.2 MB 71.2 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-22049 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-22049 | HTTPS FTP |
-Related structure data
Related structure data | 6x5cMC 6opnC 6opoC 6oppC 6opqC 6x5bC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_22049.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | sharpened map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.15 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_22049_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: Half map 2
File | emd_22049_half_map_1.map | ||||||||||||
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Annotation | Half map 2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map 1
File | emd_22049_half_map_2.map | ||||||||||||
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Annotation | Half map 1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : B41 HIV-1 Env SOSIP in complex with soluble CD4, 17b Fab, and sma...
Entire | Name: B41 HIV-1 Env SOSIP in complex with soluble CD4, 17b Fab, and small molecule GO52 |
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Components |
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-Supramolecule #1: B41 HIV-1 Env SOSIP in complex with soluble CD4, 17b Fab, and sma...
Supramolecule | Name: B41 HIV-1 Env SOSIP in complex with soluble CD4, 17b Fab, and small molecule GO52 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Human immunodeficiency virus 1 |
Molecular weight | Theoretical: 630 KDa |
-Macromolecule #1: Envelope glycoprotein gp160
Macromolecule | Name: Envelope glycoprotein gp160 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Human immunodeficiency virus 1 / Strain: B41 |
Molecular weight | Theoretical: 58.872902 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARAAKKW VTVYYGVPVW KEATTTLFCA SDAKAYDTEV HNVWATHACV PTDPNPQEI VLGNVTENFN MWKNNMVEQM HEDIISLWDQ SLKPCVKLTP LCVTLNCNNV NTNNTNNSTN ATISDWEKME T GEMKNCSF ...String: MDAMKRGLCC VLLLCGAVFV SPSQEIHARF RRGARAAKKW VTVYYGVPVW KEATTTLFCA SDAKAYDTEV HNVWATHACV PTDPNPQEI VLGNVTENFN MWKNNMVEQM HEDIISLWDQ SLKPCVKLTP LCVTLNCNNV NTNNTNNSTN ATISDWEKME T GEMKNCSF NVTTSIRDKI KKEYALFYKL DVVPLENKNN INNTNITNYR LINCNTSVIT QACPKVSFEP IPIHYCAPAG FA ILKCNSK TFNGSGPCTN VSTVQCTHGI RPVVSTQLLL NGSLAEEEIV IRSENITDNA KTIIVQLNEA VEINCTRPNN NTR KSIHIG PGRAFYATGD IIGNIRQAHC NISKARWNET LGQIVAKLEE QFPNKTIIFN HSSGGDPEIV THSFNCGGEF FYCN TTPLF NSTWNNTRTD DYPTGGEQNI TLQCRIKQII NMWQGVGKAM YAPPIRGQIR CSSNITGLLL TRDGGRDQNG TETFR PGGG NMRDNWRSEL YKYKVVKIEP LGIAPTACKR RVVQRRRRRR |
-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 / Strain: B41 |
Molecular weight | Theoretical: 17.357824 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: AVGLGAFILG FLGAAGSTMG AASMALTVQA RLLLSGIVQQ QNNLLRAPEA QQHMLQLTVW GIKQLQARVL AVERYLRDQQ LLGIWGCSG KIICCTNVPW NDSWSNKTIN EIWDNMTWMQ WEKEIDNYTQ HIYTLLEVSQ IQQEKNEQEL LELD |
-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: 23.039172 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: METDTLLLWV LLLWVPGSTG KKVVLGKKGD TVELTCTASQ KKSIQFHWKN SNQIKILGNQ GSFLTKGPSK LNDRADSRRS LWDQGNFPL IIKNLKIEDS DTYICEVEDQ KEEVQLLVFG LTANSDTHLL QGQSLTLTLE SPPGSSPSVQ CRSPRGKNIQ G GKTLSVSQ ...String: METDTLLLWV LLLWVPGSTG KKVVLGKKGD TVELTCTASQ KKSIQFHWKN SNQIKILGNQ GSFLTKGPSK LNDRADSRRS LWDQGNFPL IIKNLKIEDS DTYICEVEDQ KEEVQLLVFG LTANSDTHLL QGQSLTLTLE SPPGSSPSVQ CRSPRGKNIQ G GKTLSVSQ LELQDSGTWT CTVLQNQKKV EFKIDIVVLA GGSGHHHHHH |
-Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 23 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #7: N-(4'-methyl[1,1'-biphenyl]-4-yl)-1-oxa-7-azaspiro[3.5]nonane-7-c...
Macromolecule | Name: N-(4'-methyl[1,1'-biphenyl]-4-yl)-1-oxa-7-azaspiro[3.5]nonane-7-carboxamide type: ligand / ID: 7 / Number of copies: 3 / Formula: UOV |
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Molecular weight | Theoretical: 336.427 Da |
Chemical component information | ChemComp-UOV: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.5 mg/mL | ||||||||||||
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Buffer | pH: 7.4 Component:
Details: Detergent diluted into sample shortly before application to grid | ||||||||||||
Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 36000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 2654 / Average exposure time: 11.5 sec. / Average electron dose: 49.0 e/Å2 |
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |