04:37pm Saturday 23 September 2017

Two papers in Nature revealing the receptor activation mechanism for opioid and morphinan analgesics

Opioid receptors are highly versatile signaling molecules. Activation of the mOR results in signalling through the heterotrimeric G protein Gi, resulting in analgesia and sedation as well as euphoria and physical dependence3. The mOR can also signal through arrestin, and this pathway has been attributed to adverse effects of opioid analgesics including tolerance, respiratory suppression, and constipation.
An international team of scientists amongst whom Jan Steyaert and Toon Laeremans (VIB/Vrije Universiteit Brussel) have unraveled the structural basis for mORactivation. In two Nature papers, they report on the X-ray and NMR structures of the agonist-bound mOR receptor, stabilized in its fully activated state by use of a G protein mimetic camelid antibody fragment.
              “This knowledge may pave the way to new morphine-like
               pain killers with fewer side effects.”
                 Jan Steyaert
Structural insights into m-opioid receptor activation
Weijiao Huang, Aashish Manglik, A. J. Venkatakrishnan, Toon Laeremans, Evan N. Feinberg, Adrian L. Sanborn, Hideaki E. Kato, Kathryn E. Livingston, Thor S. Thorsen, Ralf C. Kling, Sebastien Granier, Peter Gmeiner, Stephen M. Husbands, John R. Traynor, William I. Weis, Jan Steyaert, Ron O. Dror & Brian K. Kobilka
Nature 2015 – doi:10.1038/nature14886
Propagation of conformational changes during m-opioid receptor activation
Remy Sounier, Camille Mas, Jan Steyaert, Toon Laeremans, Aashish Manglik, Weijiao Huang, Brian K. Kobilka, Helene Demene & Sebastien Granier
Nature 2015 –  doi:10.1038/nature14680


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