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  • Title: To probe interaction of morphine and IBNtxA with 7TM and 6TM variants of the human μ-opioid receptor using all-atom molecular dynamics simulations with an explicit membrane.
    Author: Sader S, Anant K, Wu C.
    Journal: Phys Chem Chem Phys; 2018 Jan 17; 20(3):1724-1741. PubMed ID: 29265141.
    Abstract:
    IBNtxA, a morphine derivative, is 10-fold more potent and has a better safety profile than morphine. Animal studies indicate that the analgesic effect of IBNtxA appears to be mediated by the activation of truncated splice variants (6TM) of the Mu opioid receptor (MOR-1) where transmembrane helix 1 (TM1) is removed. Interestingly, morphine is unable to activate 6TM variants. To date, a high resolution structure of 6TM variants is missing, and the interaction of 6TM variants with IBNtxA and morphine remains elusive. In this study we used homology modeling, docking and molecular dynamics (MD) simulations to study a representative 6TM variant (G1) and a full-length 7TM variant of human MOR-1 in complex with IBNtxA and morphine respectively. The structural models of human G1 and 7TM were obtained by homology modeling using the X-ray solved crystal structure of the active mouse 7TM bound to an agonist BU72 (PDB id: ) as the template. Our 6000 ns MD data show that either TM1 truncation (i.e. from 7TM to 6TM) or ligand modification (i.e. from morphine to IBNtxA) alone causes the loss of key morphine-7TM interactions that are well-known to be required for MOR-1 activation. Receptor disruptions are mainly located at TMs 2, 3, 6 and 7 in comparison with the active crystal complex. However, when both perturbations occur in the 6TM-IBNtxA complex, the key ligand-receptor interactions and the receptor conformation are recovered to resemble those in the active 7TM-morphine complex. Our molecular switch analysis further explains well why morphine is not able to activate 6TM variants. The close resemblance between 6TM-IBTtxA and 7TM in complex with PZM21, a G-protein biased 7TM agonist, suggests the possible biased agonism of IBNtxA on G1, which is consistent with its reduced side effects.
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