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Probe interaction of morphine and IBNtxA to 7TM and 6TM variants of human µ-opioid receptor using all-atom molecular dynamics simulation with explicit membrane

Abstract

IBNtxA, a morphine derivative, is 10-fold more potent and has a better safety profile than morphine. The animal studies indicate that the IBNtxA analgesia appears to be mediated by activation of the truncated spice variants (6TM) of 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 by IBNtxA and morphine remains to be elusive. In this study we used homology modeling, docking and molecular dynamics (MD) simulations to study a representative 6TM variant (G1) and the full-length 7TM of human MOR-1 in complex with IBNtxA and Morphine respectively. The structure models of human G1 and 7TM were obtained by homology modeling using the X-ray solved crystal structure of an active mouse 7TM bound to an agonist BU72 (PDB id: 5C1M) as the template. Our 6000 ns MD data shows that either the 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 the MOR-1 activation. The receptor disruption are mainly located at TMs 2, 3, 6 and 7 by comparing with the active crystal complex. However, when both perturbations occur in 6TM-IBNtxA complex, the key ligand-receptor interactions and the receptor conformation are recovered to resemble those in the active 7TM-morphine. Our molecular switch analysis further explains well why Morphine is not able to activate 6TM variants. The close resemble between 6TM-IBTtxA and 7TM in complex with PZM21, a G-protein biased 7TM agonist suggest a possible biased agonism of IBNtxA on G1, which is consistent with its reduced side effects.

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Publication details

The article was received on 02 Oct 2017, accepted on 05 Dec 2017 and first published on 05 Dec 2017


Article type: Paper
DOI: 10.1039/C7CP06745C
Citation: Phys. Chem. Chem. Phys., 2017, Accepted Manuscript
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    Probe interaction of morphine and IBNtxA to 7TM and 6TM variants of human µ-opioid receptor using all-atom molecular dynamics simulation with explicit membrane

    S. Sader, K. Anant and C. Wu, Phys. Chem. Chem. Phys., 2017, Accepted Manuscript , DOI: 10.1039/C7CP06745C

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