Structures of mu-opioid and delta-opioid receptors
Brian Kobilka group (Stanford University) and collaborators
The group of Brian Kobilka and collaborators have determined
structures of two of the four types of opioid receptors, as featured in the
journal, Nature, along with publications on the two other types of opioid
receptors from the group of Ray Stevens and collaborators. Opium extracts
have been used for therapeutic and recreational purposes for thousands of
years. Morphine and codeine are the main active opioid alkaloids in opium.
In humans, opioids act on the central nervous system to produce a wide range
of effects including analgesia, euphoria, sedation, and respiratory
depression. The majority of the effects of opioid alkaloids, whether
beneficial or adverse, are mediated by the mu-opioid receptor, a GPCR having
two closely related family members known as the delta- and kappa-opioid
receptors and a more distant relative known as the nociceptin/orphanin FQ
receptor. The structures of the mu-opioid receptor and of the delta-opioid
receptor provide insights into conserved elements of opioid ligand
recognition while also revealing structural features associated with ligand
subtype selectivity. The high-resolution insights into opioid receptor
structure will enable the application of structure-based approaches to
develop better drugs for the management of pain and addiction.
Figure: A transparent surface view of
the mu-opioid receptor dimer shows the covalent agonist beta-funaltrexamine
as yellow spheres in binding pockets of the crystallized dimer.
Manglik, A, Kruse, AC, Kobilka, TS, Thian, FS, Mathiesen, JM, Sunahara, RK,
Pardo, L, Weis, WI, Kobilka, BK, Granier, S. Crystal structure of the
mu-opioid receptor bound to a morphinan antagonist, Nature 485, 321-326
(2012). Granier, S, Manglik, A, Kruse, AC, Kobilka, TS, Thian, FS, Weis, WI,
Kobilka, BK. Structure of the delta-opioid receptor bound to naltrindole,
Nature 485, 400-404 (2012).