Abstract

According to the CDC, common opioid painkillers kill twice as many people as cocaine and five times as many as heroin. They cause addiction, detrimental side effects, and become less effective over time, motivating chemists to seek less flawed painkillers. This quest is being pursued through the investigation of G‐­protein‐­coupled μ‐­opioid receptors (μ­‐OR). These μ‐­ORs are composed of seven amphipathic alpha helices that span the hydrophobic middle of the cellular membrane; extending into the hydrophilic exterior and interior regions of the cell. The Longmont High School SMART (Students Modeling A Research Topic) Team modeled the μ‐­OR using 3D modeling technology. Opioid ligands are bound deeply in the solvent exposed site of the ­μ­‐OR, perhaps altering its tertiary structure. A significant feature of the μ‐­OR is the crystallization of the protein, which shows formation of a dimer resulting in complementary, interlocking structures between transmembrane segments T5 and T6 that may elicit different reactions to binding opioids. The μ­‐OR may be manipulated by agonists such as morphine, and antagonists like naloxone, due to its large and deep active site, allowing for differential specificity of reversible reactions. Active μ‐­OR receptors couple with Gi, the inhibitory G protein for adenylyl cyclase, and arrestins. Activation of arrestins produce side effects including drug tolerance, respiratory problems, and constipation. Further investigation of this μ‐­OR receptor and its signaling pathways may help biochemists find a potent painkiller with minimal side effects.

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