Mu-type opioid receptor (MOR) I322A mutant (MOR I322A)

The Mu-opioid receptor I322A mutant is a site-directed variant of the Mu-type opioid receptor (MOR), the primary molecular target for opioid analgesics such as morphine and fentanyl (UniProt P35372). This mutation involves the substitution of isoleucine with alanine at position 322, a residue located in the seventh transmembrane helix (TM7) that is critical for the receptor's conformational transition from an inactive to an active state (Huang et al., 2015, Nature). The I322 residue (position 7.39 in the Ballesteros-Weinstein system) is part of a conserved hydrophobic network that stabilizes the receptor's structure, and its mutation is frequently studied to elucidate the mechanisms of G-protein coupling and biased signaling (Manglik et al., 2012, Nature). Researchers use the I322A mutant as a tool to explore how specific amino acid side chains contribute to the efficacy and potency of various opioid ligands. By altering the internal packing of the receptor, the I322A mutation can shift the signaling profile, providing insights into the development of biased agonists that might offer pain relief without the severe side effects associated with traditional opioids, such as respiratory depression and addiction (Che et al., 2018, Cell). Although not a therapeutic target itself, the study of this mutant is essential for advancing the design of next-generation GPCR-targeted drugs.

Other names

OPRM1 I322AMu-opioid receptor I322AMOR-1 I322A

Agonist binding to the receptor induces a conformational change that activates Gi/o proteins, leading to the inhibition of adenylyl cyclase and the modulation of ion channels.