Bias-inducing allosteric binding site in mu-opioid receptor signaling
Abstract G-protein-biased agonism of the mu-opioid receptor (μ-OR) is emerging as a promising strategy in analgesia. A deep understanding of how biased agonists modulate and differentiate G-protein-coupled receptors (GPCR) signaling pathways and how this is transferred into the cell are open questio...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Springer
2021-04-01
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| Series: | SN Applied Sciences |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s42452-021-04505-8 |
| _version_ | 1818827670455058432 |
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| author | Andrés F. Marmolejo-Valencia Abraham Madariaga-Mazón Karina Martinez-Mayorga |
| author_facet | Andrés F. Marmolejo-Valencia Abraham Madariaga-Mazón Karina Martinez-Mayorga |
| author_sort | Andrés F. Marmolejo-Valencia |
| collection | DOAJ |
| description | Abstract G-protein-biased agonism of the mu-opioid receptor (μ-OR) is emerging as a promising strategy in analgesia. A deep understanding of how biased agonists modulate and differentiate G-protein-coupled receptors (GPCR) signaling pathways and how this is transferred into the cell are open questions. Here, using extensive all-atom molecular dynamics simulations, we analyzed the binding recognition process and signaling effects of three prototype μ-OR agonists. Our suggested structural mechanism of biased signaling in μ-OR involves an allosteric sodium ion site, water networks, conformational rearrangements in conserved motifs and collective motions of loops and transmembrane helices. These analyses led us to highlight the relevance of a bias-inducing allosteric binding site in the understanding of μ-OR’s G-protein-biased signaling. These results also suggest a competitive equilibrium between the agonists and the allosteric sodium ion, where the bias-inducing allosteric binding site can be modulated by this ion or an agonist such as herkinorin. Notably, herkinorin arises as the archetype modulator of μ-OR and its interactive pattern could be used for screening efforts via protein–ligand interaction fingerprint (PLIF) studies. Article highlights Agonists and a sodium ion compete for the bias-inducing allosteric binding site that modulates signaling in mu-opioid receptors. Molecular dynamics simulations of the prototype μ-OR agonist suggest a competitive equilibrium involving the agonist and an allosteric sodium ion. Analysis of experimental data from the literature and molecular models provides the structural bases of biased agonism on μ-OR. |
| first_indexed | 2024-12-19T00:47:15Z |
| format | Article |
| id | doaj.art-6f781fbad40d49acaca8e3e14515a515 |
| institution | Directory Open Access Journal |
| issn | 2523-3963 2523-3971 |
| language | English |
| last_indexed | 2024-12-19T00:47:15Z |
| publishDate | 2021-04-01 |
| publisher | Springer |
| record_format | Article |
| series | SN Applied Sciences |
| spelling | doaj.art-6f781fbad40d49acaca8e3e14515a5152022-12-21T20:44:14ZengSpringerSN Applied Sciences2523-39632523-39712021-04-013511610.1007/s42452-021-04505-8Bias-inducing allosteric binding site in mu-opioid receptor signalingAndrés F. Marmolejo-Valencia0Abraham Madariaga-Mazón1Karina Martinez-Mayorga2Instituto de Química, Universidad Nacional Autónoma de MéxicoInstituto de Química, Universidad Nacional Autónoma de MéxicoInstituto de Química, Universidad Nacional Autónoma de MéxicoAbstract G-protein-biased agonism of the mu-opioid receptor (μ-OR) is emerging as a promising strategy in analgesia. A deep understanding of how biased agonists modulate and differentiate G-protein-coupled receptors (GPCR) signaling pathways and how this is transferred into the cell are open questions. Here, using extensive all-atom molecular dynamics simulations, we analyzed the binding recognition process and signaling effects of three prototype μ-OR agonists. Our suggested structural mechanism of biased signaling in μ-OR involves an allosteric sodium ion site, water networks, conformational rearrangements in conserved motifs and collective motions of loops and transmembrane helices. These analyses led us to highlight the relevance of a bias-inducing allosteric binding site in the understanding of μ-OR’s G-protein-biased signaling. These results also suggest a competitive equilibrium between the agonists and the allosteric sodium ion, where the bias-inducing allosteric binding site can be modulated by this ion or an agonist such as herkinorin. Notably, herkinorin arises as the archetype modulator of μ-OR and its interactive pattern could be used for screening efforts via protein–ligand interaction fingerprint (PLIF) studies. Article highlights Agonists and a sodium ion compete for the bias-inducing allosteric binding site that modulates signaling in mu-opioid receptors. Molecular dynamics simulations of the prototype μ-OR agonist suggest a competitive equilibrium involving the agonist and an allosteric sodium ion. Analysis of experimental data from the literature and molecular models provides the structural bases of biased agonism on μ-OR.https://doi.org/10.1007/s42452-021-04505-8Biased signalingGPCRMu-opioid receptorMolecular dynamics simulations |
| spellingShingle | Andrés F. Marmolejo-Valencia Abraham Madariaga-Mazón Karina Martinez-Mayorga Bias-inducing allosteric binding site in mu-opioid receptor signaling SN Applied Sciences Biased signaling GPCR Mu-opioid receptor Molecular dynamics simulations |
| title | Bias-inducing allosteric binding site in mu-opioid receptor signaling |
| title_full | Bias-inducing allosteric binding site in mu-opioid receptor signaling |
| title_fullStr | Bias-inducing allosteric binding site in mu-opioid receptor signaling |
| title_full_unstemmed | Bias-inducing allosteric binding site in mu-opioid receptor signaling |
| title_short | Bias-inducing allosteric binding site in mu-opioid receptor signaling |
| title_sort | bias inducing allosteric binding site in mu opioid receptor signaling |
| topic | Biased signaling GPCR Mu-opioid receptor Molecular dynamics simulations |
| url | https://doi.org/10.1007/s42452-021-04505-8 |
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