[English] 日本語

- PDB-8czz: Cryo-EM structure of T/F100 SOSIP.664 HIV-1 Env trimer with LMHS ... -
+
Open data
-
Basic information
Entry | Database: PDB / ID: 8czz | ||||||
---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of T/F100 SOSIP.664 HIV-1 Env trimer with LMHS mutations in complex with Temsavir, 8ANC195, and 10-1074 | ||||||
![]() |
| ||||||
![]() | VIRAL PROTEIN/INHIBITOR / T/F100 SOSIP / Clade A/E HIV-1 / 8ANC195 / 10-1074 / BMS-626529 / Temsavir / LMHS mutant. / VIRAL PROTEIN-INHIBITOR complex | ||||||
Function / homology | ![]() positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / : / viral envelope / virion attachment to host cell ...positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / : / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / membrane Similarity search - Function | ||||||
Biological species | ![]() ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.14 Å | ||||||
![]() | Chen, Y. / Pozharski, E. / Tolbert, W. / Pazgier, M. | ||||||
Funding support | ![]()
| ||||||
![]() | ![]() 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 |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 614.4 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 495.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 3.4 MB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 3.5 MB | Display | |
Data in XML | ![]() | 108.7 KB | Display | |
Data in CIF | ![]() | 159.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 27103MC ![]() 8dokC ![]() 8g6uC ![]() 8ttwC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
-Protein , 2 types, 6 molecules AEIBFJ
#1: Protein | Mass: 54784.176 Da / Num. of mol.: 3 / Mutation: H61Y/Q105H/V108I/N474D/I475M/K476R/H375S Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #2: Protein | Mass: 17389.781 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
---|
-Antibody , 4 types, 12 molecules CGKDHLMOQNPR
#3: Antibody | Mass: 25324.402 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #4: Antibody | Mass: 23460.047 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #5: Antibody | Mass: 25661.688 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #6: Antibody | Mass: 23180.760 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
---|
-Sugars , 8 types, 61 molecules 
#7: Polysaccharide | Type: oligosaccharide / Mass: 1559.386 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source #8: Polysaccharide | Source method: isolated from a genetically manipulated source #9: Polysaccharide | Source method: isolated from a genetically manipulated source #10: 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 #11: 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 #12: Polysaccharide | alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[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 #13: Polysaccharide | alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-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 #15: Sugar | ChemComp-NAG / |
---|
-Non-polymers , 1 types, 3 molecules 
#14: Chemical |
---|
-Details
Has ligand of interest | Y |
---|---|
Has protein modification | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-
Sample preparation
Component | 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 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. Entity ID: #1-#6 / Source: MULTIPLE SOURCES |
---|---|
Molecular weight | Value: 6.3 MDa / Experimental value: YES |
Source (natural) | Organism: ![]() ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.4 |
Specimen | Conc.: 0.93 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K |
-
Electron microscopy imaging
Microscopy | Model: TFS GLACIOS |
---|---|
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2700 nm / Nominal defocus min: 500 nm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Electron dose: 58.14 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 1484 |
-
Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Particle selection | Num. of particles selected: 234547 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C3 (3 fold cyclic) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 234547 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | 3D fitting-ID: 1 / Source name: PDB / Type: experimental model
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement | Highest resolution: 3.14 Å |