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Article Dans Une Revue Journal of Biomolecular Structure and Dynamics Année : 2020

Exploration of the effects of sequence variations between HIV-1 and HIV-2 proteases on their three-dimensional structures

Résumé

HIV protease inhibitors (PIs) approved by the FDA (US Food and Drug Administration) are a major class of antiretroviral. HIV-2 protease (PR2) is naturally resistant to most of them as PIs were designed for HIV-1 protease (PR1). In this study, we explored the impact of amino-acid substitutions between PR1 and PR2 on the structure of protease (PR) by comparing the structural variability of 13 regions using 24 PR1 and PR2 structures complexed with diverse ligands. Our analyses confirmed structural rigidity of the catalytic region and highlighted the important role of three regions in the conservation of the catalytic region conformation. Surprisingly, we showed that the flap region, corresponding to a flexible region, exhibits similar conformations in PR1 and PR2. Furthermore, we identified regions exhibiting different conformations in PR1 and PR2, which could be explained by the intrinsic flexibility of these regions, by crystal packing, or by PR1 and PR2 substitutions. Some substitutions induce structural changes in the R2 and R4 regions that could have an impact on the properties of PI-binding site and could thus modify PI binding mode. Substitutions involved in structural changes in the elbow region could alter the flexibility of the PR2 flap regions relative to PR1, and thus play a role in the transition from the semi-open form to the closed form, and have an impact on ligand binding. These results improve the understanding of the impact of sequence variations between PR1 and PR2 on the natural resistance of HIV-2 to commercially available PIs. Communicated by Ramaswamy H. Sarma
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Dates et versions

hal-03201561 , version 1 (16-11-2022)

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Dhoha Triki, Maxime Kermarrec, Benoit Visseaux, Diane Descamps, Delphine Flatters, et al.. Exploration of the effects of sequence variations between HIV-1 and HIV-2 proteases on their three-dimensional structures. Journal of Biomolecular Structure and Dynamics, 2020, 38 (17), pp.5014-5026. ⟨10.1080/07391102.2019.1704877⟩. ⟨hal-03201561⟩
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