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Conformational flexibility of the conserved hydrophobic pocket of HIV-1 gp41. Implications for the discovery of small-molecule fusion inhibitors
- Source :
- International Journal of Biological Macromolecules. 192:90-99
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- During HIV-1 infection, the envelope glycoprotein subunit gp41 folds into a six-helix bundle structure (6HB) formed by the interaction between its N-terminal (NHR) and C-terminal (CHR) heptad-repeats, promoting viral and cell membranes fusion. A highly preserved, hydrophobic pocket (HP) on the NHR surface is crucial in 6HB formation and, therefore, HP-binding compounds constitute promising therapeutics against HIV-1. Here, we investigated the conformational and dynamic properties of the HP using a rationally designed single-chain protein (named covNHR) that mimics the gp41 NHR structure. We found that the fluorescent dye 8-anilino-naphtalene- 1-sulfonic acid (ANS) binds specifically to the HP, suggesting that ANS derivatives may constitute lead compounds to inhibit 6HB formation. ANS shows different binding modes to the HP, depending on the occupancy of other NHR pockets. Moreover, in presence of a CHR peptide bound to the N-terminal pockets in gp41, two ANS molecules can occupy the HP showing cooperative behavior. This binding mode was assessed using molecular docking and molecular dynamics simulations. The results show that the HP is conformationally flexible and connected allosterically to other NHR regions, which strongly influence the binding of potential ligands. These findings could guide the development of small-molecule HIV-1 inhibitors targeting the HP.<br />Spanish State Research Agency, SRA/ 10.13039/501100011033 (grants BIO2016-76640-R and PID2019.107515RB.C21)<br />ERDF/ESF
- Subjects :
- Models, Molecular
Binding cooperativity
Protein Conformation
Stereochemistry
Protein subunit
Peptide
Molecular Dynamics Simulation
Calorimetry
Antiviral therapy
Gp41
Biochemistry
Molecular dynamics
HIV Fusion Inhibitors
Structural Biology
Catalytic Domain
Allosterism
Humans
Coiled-coil
Amino Acid Sequence
Molecular Biology
Conserved Sequence
chemistry.chemical_classification
Coiled coil
Binding Sites
Chemistry
Spectrum Analysis
General Medicine
Small molecule
HIV Envelope Protein gp41
Peptide Fragments
Molecular Docking Simulation
Membrane
Drug Design
Thermodynamics
Glycoprotein
Hydrophobic and Hydrophilic Interactions
Protein Binding
Subjects
Details
- ISSN :
- 01418130
- Volume :
- 192
- Database :
- OpenAIRE
- Journal :
- International Journal of Biological Macromolecules
- Accession number :
- edsair.doi.dedup.....6900c5f0ef161cbd1ba38fc0b510784d