Mechanism of antagonist ligand binding to REV-ERBα
Abstract REV-ERBα, a therapeutically promising nuclear hormone receptor, plays a crucial role in regulating various physiological processes such as the circadian clock, inflammation, and metabolism. However, the availability of chemical probes to investigate the pharmacology of this receptor is limi...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-58945-4 |
| _version_ | 1797209404428255232 |
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| author | Mohammad Homaidur Rahman Lamees Hegazy |
| author_facet | Mohammad Homaidur Rahman Lamees Hegazy |
| author_sort | Mohammad Homaidur Rahman |
| collection | DOAJ |
| description | Abstract REV-ERBα, a therapeutically promising nuclear hormone receptor, plays a crucial role in regulating various physiological processes such as the circadian clock, inflammation, and metabolism. However, the availability of chemical probes to investigate the pharmacology of this receptor is limited, with SR8278 being the only identified synthetic antagonist. Moreover, no X-ray crystal structures are currently available that demonstrate the binding of REV-ERBα to antagonist ligands. This lack of structural information impedes the development of targeted therapeutics. To address this issue, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to investigate the binding pathway of SR8278 to REV-ERBα. For comparison, we also used GaMD to observe the ligand binding process of STL1267, for which an X-ray structure is available. GaMD simulations successfully captured the binding of both ligands to the receptor’s orthosteric site and predicted the ligand binding pathway and important amino acid residues involved in the antagonist SR8278 binding. This study highlights the effectiveness of GaMD in investigating protein–ligand interactions, particularly in the context of drug recognition for nuclear hormone receptors. |
| first_indexed | 2024-04-24T09:54:10Z |
| format | Article |
| id | doaj.art-4b2eead9e4ac42958433a47b233c4d7e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T09:54:10Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-4b2eead9e4ac42958433a47b233c4d7e2024-04-14T11:12:08ZengNature PortfolioScientific Reports2045-23222024-04-0114111010.1038/s41598-024-58945-4Mechanism of antagonist ligand binding to REV-ERBαMohammad Homaidur Rahman0Lamees Hegazy1Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences and PharmacyCenter for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences and PharmacyAbstract REV-ERBα, a therapeutically promising nuclear hormone receptor, plays a crucial role in regulating various physiological processes such as the circadian clock, inflammation, and metabolism. However, the availability of chemical probes to investigate the pharmacology of this receptor is limited, with SR8278 being the only identified synthetic antagonist. Moreover, no X-ray crystal structures are currently available that demonstrate the binding of REV-ERBα to antagonist ligands. This lack of structural information impedes the development of targeted therapeutics. To address this issue, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to investigate the binding pathway of SR8278 to REV-ERBα. For comparison, we also used GaMD to observe the ligand binding process of STL1267, for which an X-ray structure is available. GaMD simulations successfully captured the binding of both ligands to the receptor’s orthosteric site and predicted the ligand binding pathway and important amino acid residues involved in the antagonist SR8278 binding. This study highlights the effectiveness of GaMD in investigating protein–ligand interactions, particularly in the context of drug recognition for nuclear hormone receptors.https://doi.org/10.1038/s41598-024-58945-4 |
| spellingShingle | Mohammad Homaidur Rahman Lamees Hegazy Mechanism of antagonist ligand binding to REV-ERBα Scientific Reports |
| title | Mechanism of antagonist ligand binding to REV-ERBα |
| title_full | Mechanism of antagonist ligand binding to REV-ERBα |
| title_fullStr | Mechanism of antagonist ligand binding to REV-ERBα |
| title_full_unstemmed | Mechanism of antagonist ligand binding to REV-ERBα |
| title_short | Mechanism of antagonist ligand binding to REV-ERBα |
| title_sort | mechanism of antagonist ligand binding to rev erbα |
| url | https://doi.org/10.1038/s41598-024-58945-4 |
| work_keys_str_mv | AT mohammadhomaidurrahman mechanismofantagonistligandbindingtoreverba AT lameeshegazy mechanismofantagonistligandbindingtoreverba |