Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease
The use of antiretroviral drugs is accompanied by the emergence of HIV-2 resistances. Thus, it is important to elucidate the mechanisms of resistance to antiretroviral drugs. Here, we propose a structural analysis of 31 drug-resistant mutants of HIV-2 protease (PR2) that is an important target again...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/3/611 |
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| author | Pierre Laville Michel Petitjean Leslie Regad |
| author_facet | Pierre Laville Michel Petitjean Leslie Regad |
| author_sort | Pierre Laville |
| collection | DOAJ |
| description | The use of antiretroviral drugs is accompanied by the emergence of HIV-2 resistances. Thus, it is important to elucidate the mechanisms of resistance to antiretroviral drugs. Here, we propose a structural analysis of 31 drug-resistant mutants of HIV-2 protease (PR2) that is an important target against HIV-2 infection. First, we modeled the structures of each mutant. We then located structural shifts putatively induced by mutations. Finally, we compared wild-type and mutant inhibitor-binding pockets and interfaces to explore the impacts of these induced structural deformations on these two regions. Our results showed that one mutation could induce large structural rearrangements in side-chain and backbone atoms of mutated residue, in its vicinity or further. Structural deformations observed in side-chain atoms are frequent and of greater magnitude, that confirms that to fight drug resistance, interactions with backbone atoms should be favored. We showed that these observed structural deformations modify the conformation, volume, and hydrophobicity of the binding pocket and the composition and size of the PR2 interface. These results suggest that resistance mutations could alter ligand binding by modifying pocket properties and PR2 stability by impacting its interface. Our results reinforce the understanding of the effects of mutations that occurred in PR2 and the different mechanisms of PR2 resistance. |
| first_indexed | 2024-03-09T03:44:09Z |
| format | Article |
| id | doaj.art-196adc4d02ab4ad28892c2e872418241 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T03:44:09Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-196adc4d02ab4ad28892c2e8724182412023-12-03T14:35:52ZengMDPI AGMolecules1420-30492021-01-0126361110.3390/molecules26030611Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 ProteasePierre Laville0Michel Petitjean1Leslie Regad2Université de Paris, BFA, UMR 8251, CNRS, ERL U1133, Inserm, F-75013 Paris, FranceUniversité de Paris, BFA, UMR 8251, CNRS, ERL U1133, Inserm, F-75013 Paris, FranceUniversité de Paris, BFA, UMR 8251, CNRS, ERL U1133, Inserm, F-75013 Paris, FranceThe use of antiretroviral drugs is accompanied by the emergence of HIV-2 resistances. Thus, it is important to elucidate the mechanisms of resistance to antiretroviral drugs. Here, we propose a structural analysis of 31 drug-resistant mutants of HIV-2 protease (PR2) that is an important target against HIV-2 infection. First, we modeled the structures of each mutant. We then located structural shifts putatively induced by mutations. Finally, we compared wild-type and mutant inhibitor-binding pockets and interfaces to explore the impacts of these induced structural deformations on these two regions. Our results showed that one mutation could induce large structural rearrangements in side-chain and backbone atoms of mutated residue, in its vicinity or further. Structural deformations observed in side-chain atoms are frequent and of greater magnitude, that confirms that to fight drug resistance, interactions with backbone atoms should be favored. We showed that these observed structural deformations modify the conformation, volume, and hydrophobicity of the binding pocket and the composition and size of the PR2 interface. These results suggest that resistance mutations could alter ligand binding by modifying pocket properties and PR2 stability by impacting its interface. Our results reinforce the understanding of the effects of mutations that occurred in PR2 and the different mechanisms of PR2 resistance.https://www.mdpi.com/1420-3049/26/3/611drug-resistance mutationsHIV-2 proteasestructural characterizationinduced structural deformations |
| spellingShingle | Pierre Laville Michel Petitjean Leslie Regad Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease Molecules drug-resistance mutations HIV-2 protease structural characterization induced structural deformations |
| title | Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease |
| title_full | Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease |
| title_fullStr | Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease |
| title_full_unstemmed | Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease |
| title_short | Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease |
| title_sort | structural impacts of drug resistance mutations appearing in hiv 2 protease |
| topic | drug-resistance mutations HIV-2 protease structural characterization induced structural deformations |
| url | https://www.mdpi.com/1420-3049/26/3/611 |
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