1. K3036.58 in the μ opioid (MOP) receptor is important in conferring selectivity for covalent binding of β-funaltrexamine (β-FNA)
- Author
-
Lee-Yuan Liu-Chen, Lei Shi, Kelly M. DiMattio, and Chongguang Chen
- Subjects
Agonist ,Molecular model ,Protein Conformation ,Stereochemistry ,medicine.drug_class ,Narcotic Antagonists ,Receptors, Opioid, mu ,κ-opioid receptor ,Article ,Substrate Specificity ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,skin and connective tissue diseases ,Receptor ,Conserved Sequence ,Pharmacology ,Chemistry ,Lysine ,Receptors, Opioid, kappa ,Receptor antagonist ,Naltrexone ,Rats ,Molecular Docking Simulation ,body regions ,surgical procedures, operative ,Opioid ,Covalent bond ,Mutation ,μ-opioid receptor ,Extracellular Space ,Protein Binding ,medicine.drug - Abstract
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 e-amino group of K303 6.58 in the MOP receptor interacted with C O 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 C O 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.
- Published
- 2015