HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics
Copyright © 2022 Elsevier Inc. All rights reserved..
Antiretroviral drug resistance is a therapeutic obstacle for people with HIV. HIV protease inhibitors darunavir and lopinavir are recommended for resistant infections. We characterized a protease mutant (PR10x) derived from a highly resistant clinical isolate including 10 mutations associated with resistance to lopinavir and darunavir. Compared to the wild-type protease, PR10x exhibits ∼3-fold decrease in catalytic efficiency and Ki values of 2-3 orders of magnitude worse for darunavir, lopinavir, and potent investigational inhibitor GRL-519. Crystal structures of the mutant were solved in a ligand-free form and in complex with GRL-519. The structures show altered interactions in the active site, flap-core interface, hydrophobic core, hinge region, and 80s loop compared to the corresponding wild-type protease structures. The ligand-free crystal structure exhibits a highly curled flap conformation which may amplify drug resistance. Molecular dynamics simulations performed for 1 μs on ligand-free dimers showed extremely large fluctuations in the flaps for PR10x compared to equivalent simulations on PR with a single L76V mutation or wild-type protease. This analysis offers insight about the synergistic effects of mutations in highly resistant variants.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:117 |
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| Enthalten in: |
Journal of molecular graphics & modelling - 117(2022) vom: 15. Dez., Seite 108315 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wong-Sam, Andres [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.09.2022 Date Revised 02.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jmgm.2022.108315 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Wong-Sam, Andres |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics |
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| 500 | |a Date Revised 02.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Inc. All rights reserved. | ||
| 520 | |a Antiretroviral drug resistance is a therapeutic obstacle for people with HIV. HIV protease inhibitors darunavir and lopinavir are recommended for resistant infections. We characterized a protease mutant (PR10x) derived from a highly resistant clinical isolate including 10 mutations associated with resistance to lopinavir and darunavir. Compared to the wild-type protease, PR10x exhibits ∼3-fold decrease in catalytic efficiency and Ki values of 2-3 orders of magnitude worse for darunavir, lopinavir, and potent investigational inhibitor GRL-519. Crystal structures of the mutant were solved in a ligand-free form and in complex with GRL-519. The structures show altered interactions in the active site, flap-core interface, hydrophobic core, hinge region, and 80s loop compared to the corresponding wild-type protease structures. The ligand-free crystal structure exhibits a highly curled flap conformation which may amplify drug resistance. Molecular dynamics simulations performed for 1 μs on ligand-free dimers showed extremely large fluctuations in the flaps for PR10x compared to equivalent simulations on PR with a single L76V mutation or wild-type protease. This analysis offers insight about the synergistic effects of mutations in highly resistant variants | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Darunavir | |
| 650 | 4 | |a Drug resistance | |
| 650 | 4 | |a GRL-519 | |
| 650 | 4 | |a HIV Protease | |
| 650 | 4 | |a HIV/AIDS | |
| 650 | 4 | |a Lopinavir | |
| 650 | 4 | |a Molecular dynamics | |
| 650 | 4 | |a X-ray crystallography | |
| 650 | 7 | |a HIV Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Lopinavir |2 NLM | |
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| 650 | 7 | |a HIV Protease |2 NLM | |
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| 650 | 7 | |a EC 3.4.23.- |2 NLM | |
| 650 | 7 | |a Darunavir |2 NLM | |
| 650 | 7 | |a YO603Y8113 |2 NLM | |
| 700 | 1 | |a Wang, Yuan-Fang |e verfasserin |4 aut | |
| 700 | 1 | |a Kneller, Daniel W |e verfasserin |4 aut | |
| 700 | 1 | |a Kovalevsky, Andrey Y |e verfasserin |4 aut | |
| 700 | 1 | |a Ghosh, Arun K |e verfasserin |4 aut | |
| 700 | 1 | |a Harrison, Robert W |e verfasserin |4 aut | |
| 700 | 1 | |a Weber, Irene T |e verfasserin |4 aut | |
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