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Conformational flexibility of the conserved hydrophobic pocket of HIV-1 gp41. Implications for the discovery of small-molecule fusion inhibitors
dc.contributor.author | Cano Muñoz, Mario | |
dc.contributor.author | Jurado, Samuel | |
dc.contributor.author | Morel, Bertrand | |
dc.contributor.author | Conejero Lara, Francisco | |
dc.date.accessioned | 2023-03-07T09:38:15Z | |
dc.date.available | 2023-03-07T09:38:15Z | |
dc.date.issued | 2021-10-05 | |
dc.identifier.citation | Mario Cano-Muñoz... [et al.]. Conformational flexibility of the conserved hydrophobic pocket of HIV-1 gp41. Implications for the discovery of small-molecule fusion inhibitors, International Journal of Biological Macromolecules, Volume 192, 2021, Pages 90-99, ISSN 0141-8130, [https://doi.org/10.1016/j.ijbiomac.2021.09.198] | es_ES |
dc.identifier.uri | https://hdl.handle.net/10481/80448 | |
dc.description.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. | es_ES |
dc.description.sponsorship | Spanish State Research Agency, SRA/ 10.13039/501100011033 (grants BIO2016-76640-R and PID2019.107515RB.C21) | es_ES |
dc.description.sponsorship | ERDF/ESF | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Binding cooperativity | es_ES |
dc.subject | Coiled-coil | es_ES |
dc.subject | Allosterism | es_ES |
dc.subject | Calorimetry | es_ES |
dc.subject | Antiviral therapy | es_ES |
dc.title | Conformational flexibility of the conserved hydrophobic pocket of HIV-1 gp41. Implications for the discovery of small-molecule fusion inhibitors | es_ES |
dc.type | journal article | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.identifier.doi | 10.1016/j.ijbiomac.2021.09.198 | |
dc.type.hasVersion | VoR | es_ES |