K3036.58 in the μ opioid (MOP) receptor is important in conferring selectivity for covalent binding of β-funaltrexamine (β-FNA)
Copyright policy )K3036.58 in the μ opioid (MOP) receptor is important in conferring selectivity for covalent binding of β-funaltrexamine (β-FNA)
β-funaltrexamine (β-FNA) is an irreversible μ opioid (MOP) receptor antagonist and a reversible agonist of κ opioid (KOP) receptor. β-FNA binds covalently to the MOP receptor at Lys233(5.39), which is conserved among opioid receptors. Molecular docking of β-FNA showed that K303(6.58) in the MOP receptor and E297(6.58) in the KOP receptor played distinct roles in positioning β-FNA. K303(6.58)E MOP receptor and E297(6.58)K KOP receptor mutants were generated. The mutations did not affect β-FNA affinity or efficacy. K303(6.58)E mutation in the MOP receptor greatly reduced covalent binding of [(3)H]β-FNA; however, E297(6.58)K did not enable the KOP receptor to bind irreversibly to β-FNA. Molecular modeling demonstrated that the ε-amino group of K303(6.58) in the MOP receptor interacted with CO of the acetate group of β-FNA to facilitate covalent bond formation with Lys233(5.39). Replacement of K303(6.58) with Glu in the MOP receptor resulted in repulsion between the COOH of Glu and the CO of β-FNA and increased the distance between K233(5.39) and the fumarate group, making it impossible for covalent bond formation. These findings will be helpful for design of selective non-peptide MOP receptor antagonists.
- Cornell University United States
- Temple University United States
Protein Conformation, Lysine, Narcotic Antagonists, Receptors, Opioid, kappa, Receptors, Opioid, mu, Naltrexone, Rats, Substrate Specificity, Molecular Docking Simulation, Mice, Cell Line, Tumor, Mutation, Animals, Humans, Extracellular Space, Conserved Sequence, Protein Binding
Protein Conformation, Lysine, Narcotic Antagonists, Receptors, Opioid, kappa, Receptors, Opioid, mu, Naltrexone, Rats, Substrate Specificity, Molecular Docking Simulation, Mice, Cell Line, Tumor, Mutation, Animals, Humans, Extracellular Space, Conserved Sequence, Protein Binding
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