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Yorodumi- EMDB-27103: Cryo-EM structure of T/F100 SOSIP.664 HIV-1 Env trimer with LMHS ... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-27103 | |||||||||
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Title | Cryo-EM structure of T/F100 SOSIP.664 HIV-1 Env trimer with LMHS mutations in complex with Temsavir, 8ANC195, and 10-1074 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | T/F100 SOSIP / Clade A/E HIV-1 / 8ANC195 / 10-1074 / BMS-626529 / Temsavir / LMHS mutant. / VIRAL PROTEIN-INHIBITOR 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 / apoptotic process / host cell plasma membrane / structural molecule activity / virion membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Severe acute respiratory syndrome coronavirus 2 / Human immunodeficiency virus 1 / Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.14 Å | |||||||||
Authors | Chen Y / Pozharski E / Tolbert W / Pazgier M | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Nat Commun / Year: 2023 Title: Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir. Authors: Jérémie Prévost / Yaozong Chen / Fei Zhou / William D Tolbert / Romain Gasser / Halima Medjahed / Manon Nayrac / Dung N Nguyen / Suneetha Gottumukkala / Ann J Hessell / Venigalla B Rao / ...Authors: Jérémie Prévost / Yaozong Chen / Fei Zhou / William D Tolbert / Romain Gasser / Halima Medjahed / Manon Nayrac / Dung N Nguyen / Suneetha Gottumukkala / Ann J Hessell / Venigalla B Rao / Edwin Pozharski / Rick K Huang / Doreen Matthies / Andrés Finzi / Marzena Pazgier / Abstract: The HIV-1 entry inhibitor temsavir prevents the viral receptor CD4 (cluster of differentiation 4) from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do ...The HIV-1 entry inhibitor temsavir prevents the viral receptor CD4 (cluster of differentiation 4) from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do this, temsavir relies on the presence of a residue with small side chain at position 375 in Env and is unable to neutralize viral strains like CRF01_AE carrying His375. Here we investigate the mechanism of temsavir resistance and show that residue 375 is not the sole determinant of resistance. At least six additional residues within the gp120 inner domain layers, including five distant from the drug-binding pocket, contribute to resistance. A detailed structure-function analysis using engineered viruses and soluble trimer variants reveals that the molecular basis of resistance is mediated by crosstalk between His375 and the inner domain layers. Furthermore, our data confirm that temsavir can adjust its binding mode to accommodate changes in Env conformation, a property that likely contributes to its broad antiviral activity. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_27103.map.gz | 122.4 MB | EMDB map data format | |
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Header (meta data) | emd-27103-v30.xml emd-27103.xml | 25.2 KB 25.2 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_27103_fsc.xml | 14.8 KB | Display | FSC data file |
Images | emd_27103.png | 194.4 KB | ||
Filedesc metadata | emd-27103.cif.gz | 7.7 KB | ||
Others | emd_27103_half_map_1.map.gz emd_27103_half_map_2.map.gz | 109.6 MB 109.6 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-27103 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-27103 | HTTPS FTP |
-Validation report
Summary document | emd_27103_validation.pdf.gz | 868.2 KB | Display | EMDB validaton report |
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Full document | emd_27103_full_validation.pdf.gz | 867.7 KB | Display | |
Data in XML | emd_27103_validation.xml.gz | 18.9 KB | Display | |
Data in CIF | emd_27103_validation.cif.gz | 24.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27103 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27103 | HTTPS FTP |
-Related structure data
Related structure data | 8czzMC 8dokC 8g6uC 8ttwC 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_27103.map.gz / Format: CCP4 / Size: 129.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.8893 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_27103_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_27103_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Cryo-EM structure of T/F100 SOSIP.664 HIV-1 Env trimer with LMHS ...
Entire | Name: Cryo-EM structure of T/F100 SOSIP.664 HIV-1 Env trimer with LMHS mutations in complex with Temsavir, 8ANC195, and 10-1074 |
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Components |
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-Supramolecule #1: Cryo-EM structure of T/F100 SOSIP.664 HIV-1 Env trimer with LMHS ...
Supramolecule | Name: Cryo-EM structure of T/F100 SOSIP.664 HIV-1 Env trimer with LMHS mutations in complex with Temsavir, 8ANC195, and 10-1074 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6 Details: LM mutations refer to layer mutants (H61Y/Q105H/V108I/N474D/I475M/K476R) and HS mutation refer to H375S. Temsavir (BMS-626529) is a novel small-molecule HIV-1 attachment inhibitor. |
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Source (natural) | Organism: Severe acute respiratory syndrome coronavirus 2 |
Molecular weight | Theoretical: 6.3 MDa |
-Macromolecule #1: CRF01_AE T/F100 HIV-1 gp120
Macromolecule | Name: CRF01_AE T/F100 HIV-1 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: 54.784176 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: ATNNLWVTVY YGVPVWRDAD TTLFCASDAK AYETEVHNVW ATHACVPTDP NPQEMHLKNV TENFNMWKNN MVEQMHEDII SLWDQSLKP CVKLTPLCVT LNCTSATVTN YTKVNDTSDI IGNITDDVRN CSFNMTTELR DKQQKVYALF YKLDIVPIDD S SNNGSSNF ...String: ATNNLWVTVY YGVPVWRDAD TTLFCASDAK AYETEVHNVW ATHACVPTDP NPQEMHLKNV TENFNMWKNN MVEQMHEDII SLWDQSLKP CVKLTPLCVT LNCTSATVTN YTKVNDTSDI IGNITDDVRN CSFNMTTELR DKQQKVYALF YKLDIVPIDD S SNNGSSNF SEYRLINCNT SVIKQACPKV SFDPIPIHYC TPAGYAILRC NDKKFNGTGP CKNVSSVQCT HGIKPVVSTQ LL LNGSLAE EGIIIRSENL TNNAKTIIVH FNESVKINCT RPSNNTRTGI HIGPGQVFYK TGDIIGDIRK AYCNISGAQW HKV LGRVAN KLKEHFNNKT IVFKPSSGGD PEITMHSFNC RGEFFYCNTT KLFNSTWGGN KNETRDNGTI TIPCRIKQII NMWQ GVGQA MYAPPIKGVI KCLSNITGIL LTRDGGNDST ENNETFRPGG GDMRDNWRNE LYKYKVVQIE PLGIAPTKCK RRVVE RRRR RR UniProtKB: Envelope glycoprotein gp160 |
-Macromolecule #2: CRF-1_AE T/F100 HIV-1 gp41
Macromolecule | Name: CRF-1_AE T/F100 HIV-1 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: 17.389781 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: AVGLGAMIFG FLGAAGSTMG AASITLTVQA RQLLSGIVQQ QSNLLRAPEA QQHLLQLTVW GIKQLQARVL AVERYLQDQK FLGLWGCSG KIICCTAVPW NSSWSNKTFE EIWNNMTWIE WEREISNYTS QIYDILTISQ TQQEKNEKDL LELDAA UniProtKB: Envelope glycoprotein gp160 |
-Macromolecule #3: Heavy chain of 8ANC195 Fab
Macromolecule | Name: Heavy chain of 8ANC195 Fab / 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: 25.324402 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: QIHLVQSGTE VKKPGSSVTV SCKAYGVNTF GLYAVNWVRQ APGQSLEYIG QIWRWKSSAS HHFRGRVLIS AVDLTGSSPP ISSLEIKNL TSDDTAVYFC TTTSTYDRWS GLHHDGVMAF SSWGQGTLIS VSAASTKGPS VFPLAPSSKS TSGGTAALGC L VKDYFPEP ...String: QIHLVQSGTE VKKPGSSVTV SCKAYGVNTF GLYAVNWVRQ APGQSLEYIG QIWRWKSSAS HHFRGRVLIS AVDLTGSSPP ISSLEIKNL TSDDTAVYFC TTTSTYDRWS GLHHDGVMAF SSWGQGTLIS VSAASTKGPS VFPLAPSSKS TSGGTAALGC L VKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK RVEPKSCDKT |
-Macromolecule #4: Light chain of 8ANC195 Fab
Macromolecule | Name: Light chain of 8ANC195 Fab / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 23.460047 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: DIQMTQSPST LSASTGDTVR ISCRASQSIT GNWVAWYQQR PGKAPRLLIY RGAALLGGVP SRFRGSAAGT DFTLTIGNLQ AEDFGTFYC QQYDTYPGTF GQGTKVEVKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String: DIQMTQSPST LSASTGDTVR ISCRASQSIT GNWVAWYQQR PGKAPRLLIY RGAALLGGVP SRFRGSAAGT DFTLTIGNLQ AEDFGTFYC QQYDTYPGTF GQGTKVEVKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC |
-Macromolecule #5: Heavy chain of 10-1074 Fab
Macromolecule | Name: Heavy chain of 10-1074 Fab / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 25.661688 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: QVQLQESGPG LVKPSETLSV TCSVSGDSMN NYYWTWIRQS PGKGLEWIGY ISDRESATYN PSLNSRVVIS RDTSKNQLSL KLNSVTPAD TAVYYCATAR RGQRIYGVVS FGEFFYYYSM DVWGKGTTVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC L VKDYFPEP ...String: QVQLQESGPG LVKPSETLSV TCSVSGDSMN NYYWTWIRQS PGKGLEWIGY ISDRESATYN PSLNSRVVIS RDTSKNQLSL KLNSVTPAD TAVYYCATAR RGQRIYGVVS FGEFFYYYSM DVWGKGTTVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC L VKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK RVEPKSCDKT |
-Macromolecule #6: Light chain of 10-1074 Fab
Macromolecule | Name: Light chain of 10-1074 Fab / type: protein_or_peptide / ID: 6 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 23.18076 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: SYVRPLSVAL GETARISCGR QALGSRAVQW YQHRPGQAPI LLIYNNQDRP SGIPERFSGT PDINFGTRAT LTISGVEAGD EADYYCHMW DSRSGFSWSF GGATRLTVLG QPKAAPSVTL FPPSSEELQA NKATLVCLIS DFYPGAVTVA WKADSSPVKA G VETTTPSK ...String: SYVRPLSVAL GETARISCGR QALGSRAVQW YQHRPGQAPI LLIYNNQDRP SGIPERFSGT PDINFGTRAT LTISGVEAGD EADYYCHMW DSRSGFSWSF GGATRLTVLG QPKAAPSVTL FPPSSEELQA NKATLVCLIS DFYPGAVTVA WKADSSPVKA G VETTTPSK QSNNKYAASS YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS |
-Macromolecule #14: 1-[4-(benzenecarbonyl)piperazin-1-yl]-2-[4-methoxy-7-(3-methyl-1H...
Macromolecule | Name: 1-[4-(benzenecarbonyl)piperazin-1-yl]-2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]ethane-1,2-dione type: ligand / ID: 14 / Number of copies: 3 / Formula: 83J |
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Molecular weight | Theoretical: 473.484 Da |
Chemical component information | ChemComp-83J: |
-Macromolecule #15: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 15 / Number of copies: 34 / 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
Concentration | 0.93 mg/mL |
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Buffer | pH: 7.4 |
Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 0.2 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | TFS GLACIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 1484 / Average electron dose: 58.14 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.7 µm / Nominal defocus min: 0.5 µm |
Sample stage | Cooling holder cryogen: NITROGEN |
+Image processing
-Atomic model buiding 1
Initial model |
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Refinement | Space: REAL / Protocol: FLEXIBLE FIT | ||||||||||||||
Output model | PDB-8czz: |