Researchers from the Receptor Channels Group (Institut Pasteur/CNRS URA 2182) and the Structural Dynamics of Macromolecules Unit (Institut Pasteur / CNRS URA 2185), directed by Pierre-Jean Corringer and Marc Delarue, respectively, have just determined the 3D structures of two general anaesthetics, propofol and desflurane, in a complex with a molecule homologous to their binding site. This binding site is, in vivo, a channel receptor present in the cell membrane.
 | 3D model of propofol bound to a bacterial homologue of the GABAA receptor. © H. Nury/Institut Pasteur |
The researchers crystallized the complex, then analyzed its structure by X-ray diffraction, on the PROXIMA1 beamline at SOLEIL and the ID14 beamline at ESRF. Such an anaesthetic / receptor complex had never previously been observed. For this they used a bacterial homologue of the GABAA channel, which they had discovered in 2007 (1). The GABAA receptor is actually one of the key membrane targets for anaesthetic molecules. In humans, this is the main conduit for the transmission of inhibitory nerve impulses.
Using the atomic scale resolution of the complex’s structure, scientists have been able to identify the binding sites to which the anaesthetics specifically bind. They have also been able to show that it is possible to adjust both the affinity of the anaesthetic for its receptor and the activity of the receptor by slightly modifying the binding site configurations. These results corroborate data from the scientific literature suggesting that the binding of the anaesthetic molecule potentiates the inhibitory effect of the receptor, thus blocking further the transmission of nerve impulses, such as the feeling of pain, for example.
This study, published in Nature (2), provides, for the first time, high resolution structural elements underlying the action of general anaesthetics. Although, with the use of ether, their discovery two centuries ago had revolutionized surgical practice, the mechanisms underlying their action remain poorly understood.
Crossing this hurdle paves the way for the design and development, through molecular modeling technologies, of new more specific drugs, with fewer side effects.
References :
(1) Nicotine : un récepteur du passé pour développer les médicaments de demain
(2) Nury, H. et al., “X-Ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel”, Nature, 469, 428-33 (2011)
From communiqué de presse du CNRS
