Characterization of HIV-2 Protease Structure by Studying Its Asymmetry at the Different Levels of Protein Description

Ollitrault, Guillaume; Fartek, Sandrine; Descamps, Diane; Camproux, Anne-Claude; Visseaux, Benoît; Regad, Leslie

doi:10.3390/sym10110644

Cited by 4 publications

(18 citation statements)

References 42 publications

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“…Our structural-alphabet-based approach highlighted that 35% of unbound PR2 positions are asymmetric. In the unbound and bound structures, the asymmetric positions are distributed throughout the structure, particularly in the interface region and in the flap, fulcrum, elbow, and αhelix regions and the binding site [31,33]. Thus, the crystallographic PR2 structure exhibits structural asymmetry in its backbone, and this property is also found in the unbound structure.…”

Section: Introductionmentioning

confidence: 99%

“…The analyses of the crystallographic structures of PR2 have shown that the two monomers do not exhibit the same global and local conformations, indicating that in crystallographic structures, PR2 exhibits structural asymmetry [27][28][29][30][31][32]. This structural asymmetry is translated by slightly different orientation of its two monomers, quantified by a two-fold axis of 178.20°to 179.80°and a root mean square deviation (RMSD) of 0.35 to 1.02 Å [27][28][29][30]33]. The largest deviations between the two monomers are located in the tail, elbow, and flap regions [27][28][29][30][31]33].…”

Section: Introductionmentioning

confidence: 99%

“…This structural asymmetry is translated by slightly different orientation of its two monomers, quantified by a two-fold axis of 178.20°to 179.80°and a root mean square deviation (RMSD) of 0.35 to 1.02 Å [27][28][29][30]33]. The largest deviations between the two monomers are located in the tail, elbow, and flap regions [27][28][29][30][31]33]. Using a structural-alphabet-based approach, 31% of PR2 positions were identified as structurally asymmetric (i.e., exhibiting different local conformations in their two chains), among which 75% were located outside of the PIbinding pocket [31,33].…”

Section: Introductionmentioning

confidence: 99%

“…The largest deviations between the two monomers are located in the tail, elbow, and flap regions [27][28][29][30][31]33]. Using a structural-alphabet-based approach, 31% of PR2 positions were identified as structurally asymmetric (i.e., exhibiting different local conformations in their two chains), among which 75% were located outside of the PIbinding pocket [31,33]. In a recent study, we explored the structural asymmetry of unbound PR [33].…”

Section: Introductionmentioning

confidence: 99%

“…Using a structural-alphabet-based approach, 31% of PR2 positions were identified as structurally asymmetric (i.e., exhibiting different local conformations in their two chains), among which 75% were located outside of the PIbinding pocket [31,33]. In a recent study, we explored the structural asymmetry of unbound PR [33]. Its two monomers exhibit a Cα-RMSD value of 0.53 Å, which is smaller than that computed on the bound PR2 [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Impacts of drug resistance mutations on the structural asymmetry of the HIV-2 protease

Laville

Fartek

Cerisier

et al. 2020

BMC Mol and Cell Biol

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Background: Drug resistance is a severe problem in HIV treatment. HIV protease is a common target for the design of new drugs for treating HIV infection. Previous studies have shown that the crystallographic structures of the HIV-2 protease (PR2) in bound and unbound forms exhibit structural asymmetry that is important for ligand recognition and binding. Here, we investigated the effects of resistance mutations on the structural asymmetry of PR2. Due to the lack of structural data on PR2 mutants, the 3D structures of 30 PR2 mutants of interest have been modeled using an in silico protocol. Structural asymmetry analysis was carried out with an in-house structural-alphabet-based approach. Results: The systematic comparison of the asymmetry of the wild-type structure and a large number of mutants highlighted crucial residues for PR2 structure and function. In addition, our results revealed structural changes induced by PR2 flexibility or resistance mutations. The analysis of the highlighted structural changes showed that some mutations alter protein stability or inhibitor binding. Conclusions: This work consists of a structural analysis of the impact of a large number of PR2 resistant mutants based on modeled structures. It suggests three possible resistance mechanisms of PR2, in which structural changes induced by resistance mutations lead to modifications in the dimerization interface, ligand recognition or inhibitor binding.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Impacts of drug resistance mutations on the structural asymmetry of the HIV-2 protease

Laville

Fartek

Cerisier

et al. 2020

BMC Mol and Cell Biol

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

Triki

Kermarrec

Visseaux

et al. 2019

Journal of Biomolecular Structure and Dynamics

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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 PR 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 the 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.

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Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease

2021

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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.

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Characterization of HIV-2 Protease Structure by Studying Its Asymmetry at the Different Levels of Protein Description

Cited by 4 publications

References 42 publications

Impacts of drug resistance mutations on the structural asymmetry of the HIV-2 protease

Impacts of drug resistance mutations on the structural asymmetry of the HIV-2 protease

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

Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease

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