Activation Mechanism of the Morphine Receptor Revealed

A close collaboration between the team of Sebastien Granier (IGF) in Montpellier, Hélène Déméné (CBS, team "NMR, Structure, Dynamics and Function of Biomolecules by NMR") and the team of Prof. Brian Kobilka of Stanford University, Nobel Prize in Chemistry in 2012, helped to decipher the molecular mechanisms of activation of the morphine receptor. This receptor, also called mu opioid receptor (μOR) was investigated using combining X-ray crystallography and Nuclear Magnetic Resonance (NMR). The morphine receptor is a membrane protein belonging to the family of G protein coupled receptors (GPCR) whose operating mechanism is not well known. This lack of knowledge is partly due to the difficulties encountered in the investigation of these membrane proteins by structural biology approaches. This study has been published in the scientific journal Nature (Sounier et al, Nature, 524 (7565). -doi 375-8: 10.1038 / nature14680).

The NMR study reveals how the binding of a ligand that mimics morphine (agonist) induces changes in conformational states of μOR from an inactive state to an active state. This active state is the only one capable to lead to intracellular signal transduction via activation of signaling proteins such as G protein. The study also shows that the active state can be achieved only if the agonist and G protein are linked to the receiver simultaneously. This property was previously observed for only one of the 800 members that make up the family of GPCRs. Thus, the study reveals how the activation signal propagates through the different areas of the receptor and proposes that this process plays a key role in signal transduction. Overall, these data shed light on the little known process of activation of GPCRs and its dynamics.

New publication: "Propagation of conformational changes during μ-opioid receptor activation" 
Authors: Sounier R, Mas C, Steyaert J, Laeremans T, Manglik A, Huang W, Kobilka BK, Déméné H, Granier S.
Journal: Nature. 2015 Aug 20;524(7565):375-8. doi: 10.1038/nature14680.

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