Conformational landscape of non-B variants of HIV-1 protease: A pulsed EPR study
| Autor: | Gail E. Fanucci, Trang T. Tran, Zhanglong Liu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Protein Conformation Stereochemistry medicine.medical_treatment Biophysics Human immunodeficiency virus (HIV) Closed conformation medicine.disease_cause Biochemistry law.invention 03 medical and health sciences 0302 clinical medicine HIV Protease HIV-1 protease law medicine Africa Central Hiv treatment Electron paramagnetic resonance Molecular Biology Polymorphism Genetic Protease biology Chemistry Pulsed EPR Electron Spin Resonance Spectroscopy HIV Protease Inhibitors Cell Biology 030104 developmental biology 030220 oncology & carcinogenesis HIV-1 biology.protein Spin Labels Brazil |
| Zdroj: | Biochemical and Biophysical Research Communications. 532:219-224 |
| ISSN: | 0006-291X |
| Popis: | HIV infection is a global health epidemic with current FDA-approved HIV-1 Protease inhibitors (PIs) designed against subtype B protease, yet they are used in HIV treatment world-wide regardless of patient HIV classification. In this study, double electron-electron resonance (DEER) electron paramagnetic resonance (EPR) spectroscopy was utilized to gain insights in how natural polymorphisms in several African and Brazilian protease (PR) variants affect the conformational landscape both in the absence and presence of inhibitors. Findings show that Subtypes F and H HIV-1 PR adopt a primarily closed conformation in the unbound state with two secondary mutations, D60E and I62V, postulated to be responsible for the increased probability for closed conformation. In contrast, subtype D, CRF_AG, and CRF_BF HIV-1 PR adopt a primarily semi-open conformation, as observed for PI-naive-subtype B when unbound by substrate or inhibitor. The impact that inhibitor binding has on shifting the conformational land scape of these variants is also characterized, where analysis provides classification of inhibitor induced shifts away from the semi-open state into weak, moderate and strong effects. The findings are compared to those for prior studies of inhibitor induced conformational shifts in PI-naive Subtype B, C and CRF_AE. |
| Databáze: | OpenAIRE |
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