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Construction of a µ-opioid receptor model: identification of the opioid alkaloid binding pocket

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Elizabeth B. Poole (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Patricia H. Reggio

Abstract: Morphine and other analgesics bind to and activate the µ-opioid receptor (MOR). The opioid receptors belong to the Class A subfamily of G-Protein Coupled Receptors (GPCRs). These are transmembrane proteins with seven helices arranged to form a closed bundle with loops that extend both extracellularly and intracellularly. Activation of this family of GPCRs has been shown to involve the change of the ?1 dihedral of a tryptophan residue on TMH6, W6.48, from g+ to trans. The purpose of this project was to design a computational model of the MOR and to dock both morphine an agonist, and naloxone an antagonist, into the model such that their positions were consistent with their pharmacologies. A MOR model was created using the Beta-2-Adrenergic (ß 2-AR) crystal structure as a template with two major modifications. First, the Conformational Memories (CM) program was used to study the conformations of three transmembrane helices (TMH); TMH2, TMH4 and TMH6. Second, the TMH7/elbow/Hx8 region of the ß 2-AR was replaced with that of the adenosine A2A crystal structure because the adenosine A2A receptor has the same number of residues in the elbow region as is found in the MOR. Energy minimizations were performed on the MOR bundle in a three step process and the ligand binding pocket was identified. Docking studies suggested that naloxone binds in the TMH2-3-6-7 region of the MOR such that the N-allyl group sterically prohibits the movement of the ?1 of W6.48, thereby preventing activation of the receptor. Morphine was also found to bind in the TMH2-3-6-7 region of the MOR; however no portion of the morphine structure could block the movement of the ?1 of W6.48, thereby producing no impediment for activation. These results are consistent with the pharmacology of naloxone (MOR antagonist) and morphine (MOR agonist). Models created will be used for future mutation studies.

Additional Information

Language: English
Date: 2009
Computational Model, Opioids, MOR
Opioids $x Receptors.
Computational biology.
Binding sites (Biochemistry)