Dynamics of the Apo µ-Opioid Receptor in Complex with Gi Protein
Opioid receptors, particularly the µ-opioid receptor (μOR), play a pivotal role in mediating the analgesic and addictive effects of opioid drugs. G protein signaling is an important pathway of μOR function, usually associated with painkilling effects. However, the molecular mechanisms underlying the...
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/17/13430 |
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| author | Mira Raya Paula de Lima Rubem Francisco Silva Bezerra David Denis Bento Serafim Diniz Maciel Sena Junior |
| author_facet | Mira Raya Paula de Lima Rubem Francisco Silva Bezerra David Denis Bento Serafim Diniz Maciel Sena Junior |
| author_sort | Mira Raya Paula de Lima |
| collection | DOAJ |
| description | Opioid receptors, particularly the µ-opioid receptor (μOR), play a pivotal role in mediating the analgesic and addictive effects of opioid drugs. G protein signaling is an important pathway of μOR function, usually associated with painkilling effects. However, the molecular mechanisms underlying the interaction between the μOR and G protein remain poorly understood. In this study, we employed classical all-atom molecular dynamics simulations to investigate the structural changes occurring with the μOR-G protein complex under two different conditions: with the G protein in the apo form (open) and with the GDP bound G protein (closed, holo form). The receptor was in the apo form and active conformation in both cases, and the simulation time comprised 1µs for each system. In order to assess the effect of the G protein coupling on the receptor activation state, three parameters were monitored: the correlation of the distance between TM3 and TM6 and the RMSD of the NPxxYA motif; the universal activation index (A100); and the χ<sup>2</sup> dihedral distribution of residue W293<sup>6.48</sup>. When complexed with the open G protein, receptor conformations with intermediate activation state prevailed throughout the molecular dynamics, whereas in the condition with the closed G protein, mostly inactive conformations of the receptor were observed. The major effect of the G protein in the receptor conformation comes from a steric hindrance involving an intracellular loop of the receptor and a β-sheet region of the G protein. This suggests that G-protein precoupling is essential for receptor activation, but this fact is not sufficient for complete receptor activation. |
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| format | Article |
| id | doaj.art-5ad1a68badaf4894818d2dfa72ab4075 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:21:23Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5ad1a68badaf4894818d2dfa72ab40752023-11-19T08:17:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124171343010.3390/ijms241713430Dynamics of the Apo µ-Opioid Receptor in Complex with Gi ProteinMira Raya Paula de Lima0Rubem Francisco Silva Bezerra1David Denis Bento Serafim2Diniz Maciel Sena Junior3Biological Chemistry Department, Universidade Regional do Cariri—URCA, Crato 63105-000, CE, BrazilBiological Chemistry Department, Universidade Regional do Cariri—URCA, Crato 63105-000, CE, BrazilBiological Chemistry Department, Universidade Regional do Cariri—URCA, Crato 63105-000, CE, BrazilBiological Chemistry Department, Universidade Regional do Cariri—URCA, Crato 63105-000, CE, BrazilOpioid receptors, particularly the µ-opioid receptor (μOR), play a pivotal role in mediating the analgesic and addictive effects of opioid drugs. G protein signaling is an important pathway of μOR function, usually associated with painkilling effects. However, the molecular mechanisms underlying the interaction between the μOR and G protein remain poorly understood. In this study, we employed classical all-atom molecular dynamics simulations to investigate the structural changes occurring with the μOR-G protein complex under two different conditions: with the G protein in the apo form (open) and with the GDP bound G protein (closed, holo form). The receptor was in the apo form and active conformation in both cases, and the simulation time comprised 1µs for each system. In order to assess the effect of the G protein coupling on the receptor activation state, three parameters were monitored: the correlation of the distance between TM3 and TM6 and the RMSD of the NPxxYA motif; the universal activation index (A100); and the χ<sup>2</sup> dihedral distribution of residue W293<sup>6.48</sup>. When complexed with the open G protein, receptor conformations with intermediate activation state prevailed throughout the molecular dynamics, whereas in the condition with the closed G protein, mostly inactive conformations of the receptor were observed. The major effect of the G protein in the receptor conformation comes from a steric hindrance involving an intracellular loop of the receptor and a β-sheet region of the G protein. This suggests that G-protein precoupling is essential for receptor activation, but this fact is not sufficient for complete receptor activation.https://www.mdpi.com/1422-0067/24/17/13430G protein signalingmolecular dynamicsGuanosine Di-phosphate (GDP) |
| spellingShingle | Mira Raya Paula de Lima Rubem Francisco Silva Bezerra David Denis Bento Serafim Diniz Maciel Sena Junior Dynamics of the Apo µ-Opioid Receptor in Complex with Gi Protein International Journal of Molecular Sciences G protein signaling molecular dynamics Guanosine Di-phosphate (GDP) |
| title | Dynamics of the Apo µ-Opioid Receptor in Complex with Gi Protein |
| title_full | Dynamics of the Apo µ-Opioid Receptor in Complex with Gi Protein |
| title_fullStr | Dynamics of the Apo µ-Opioid Receptor in Complex with Gi Protein |
| title_full_unstemmed | Dynamics of the Apo µ-Opioid Receptor in Complex with Gi Protein |
| title_short | Dynamics of the Apo µ-Opioid Receptor in Complex with Gi Protein |
| title_sort | dynamics of the apo µ opioid receptor in complex with gi protein |
| topic | G protein signaling molecular dynamics Guanosine Di-phosphate (GDP) |
| url | https://www.mdpi.com/1422-0067/24/17/13430 |
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