Structural and Thermodynamic Analysis of HIV-1 Fusion Inhibition Using Small gp41 Mimetic Proteins
| العنوان: | Structural and Thermodynamic Analysis of HIV-1 Fusion Inhibition Using Small gp41 Mimetic Proteins |
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| المؤلفون: | Samuel Jurado, Mario Cano-Muñoz, Bertrand Morel, Sara Standoli, Elisabetta Santarossa, Christiane Moog, Sylvie Schmidt, Géraline Laumond, Ana Cámara-Artigas, Francisco Conejero-Lara |
| المساهمون: | Universidad de Granada = University of Granada (UGR), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Universidad de Almería (UAL), univOAK, Archive ouverte |
| المصدر: | Digibug. Repositorio Institucional de la Universidad de Granada instname Digibug: Repositorio Institucional de la Universidad de Granada Universidad de Granada (UGR) Journal of Molecular Biology Journal of Molecular Biology, 2019, 431 (17), pp.3091-3106. ⟨10.1016/j.jmb.2019.06.022⟩ |
| بيانات النشر: | Elsevier BV, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Models, Molecular, binding, fusion inhibitor, Anti-HIV Agents, Protein Conformation, envelope glycoprotein, Enfuvirtide, Virus Internalization, Crystallography, X-Ray, HIV Envelope Protein gp41, Sequence Analysis, Protein, Structural Biology, Mutation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, HIV-1, Thermodynamics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Peptides, calorimetry, Molecular Biology, x-ray crystallography |
| الوصف: | Development of effective inhibitors of the fusion between HIV-1 and the host cell membrane mediated by gp41 continues to be a grand challenge due to an incomplete understanding of the molecular and mechanistic details of the fusion process. We previously developed single-chain, chimeric proteins (named covNHR) that accurately mimic the N-heptad repeat (NHR) region of gp41 in a highly stable coiled-coil conformation. These molecules bind strongly to peptides derived from the gp41 C-heptad repeat (CHR) and are potent and broad HIV-1 inhibitors. Here, we investigated two covNHR variants differing in two mutations, V10E and Q123R (equivalent to V38E and Q40R in gp41 sequence) that reproduce the effect of HIV-1 mutations associated with resistance to fusion inhibitors, such as T20 (enfuvirtide). A detailed calorimetric analysis of the binding between the covNHR proteins and CHR peptides (C34 and T20) reveals drastic changes in affinity due to the mutations as a result of local changes in interactions at the site of T20 resistance. The crystallographic structure of the covNHR:C34 complex shows a virtually identical CHR–NHR binding interface to that of the post-fusion structure of gp41 and underlines an important role of buried interfacial water molecules in binding affinity and in development of resistance against CHR peptides. Despite the great difference in affinity, both covNHR variants demonstrate strong inhibitory activity for a wide variety of HIV-1 strains. These properties support the high potential of these covNHR proteins as new potent HIV-1 inhibitors. Our results may guide future inhibition approaches. Departamento de Química Física e Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain Ministerio de Economía y Competitividad (grants BIO2016-76640-R and BIO2016-78020-R) y Fondo Europeo para el Desarrollo Regional (FEDER) de la Unión Europea ANRS and the Vaccine Research Institute for the Investissements d'Avenir program managed by the ANR under reference ANR-10-LABX-77 |
| وصف الملف: | application/pdf |
| تدمد: | 0022-2836 1089-8638 |
| DOI: | 10.1016/j.jmb.2019.06.022 |
| DOI: | 10.1016/j.jmb.2019.06.022⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9931756dfefbc2b02095dbc64bd75ae6 https://doi.org/10.1016/j.jmb.2019.06.022 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9931756dfefbc2b02095dbc64bd75ae6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00222836 10898638 |
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| DOI: | 10.1016/j.jmb.2019.06.022 |