3P50

Structure of propofol bound to a pentameric ligand-gated ion channel, GLIC

Summary for 3P50

• Entry DOI: 10.2210/pdb3p50/pdb
• Related: 3P4W
• Descriptor: Glr4197 protein, DODECYL-BETA-D-MALTOSIDE, 2,6-BIS(1-METHYLETHYL)PHENOL, ... (5 entities in total)
• Functional Keywords: ligand-gated ion channel, membrane protein, transport protein
• Biological source: Gloeobacter violaceus
• Cellular location: Cell inner membrane ; Multi- pass membrane protein : Q7NDN8
• Total number of polymer chains: 5
• Total formula weight: 191927.41

Authors

Nury, H.,Van Renterghem, C.,Weng, Y.,Tran, A.,Baaden, M.,Dufresne, V.,Changeux, J.P.,Sonner, J.M.,Delarue, M.,Corringer, P.J. (deposition date: 2010-10-07, release date: 2011-01-19, Last modification date: 2023-11-01)

Primary citation

Nury, H.,Van Renterghem, C.,Weng, Y.,Tran, A.,Baaden, M.,Dufresne, V.,Changeux, J.P.,Sonner, J.M.,Delarue, M.,Corringer, P.J.
X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel
Nature, 469:428-431, 2011

PubMed Abstract: General anaesthetics have enjoyed long and widespread use but their molecular mechanism of action remains poorly understood. There is good evidence that their principal targets are pentameric ligand-gated ion channels (pLGICs) such as inhibitory GABA(A) (γ-aminobutyric acid) receptors and excitatory nicotinic acetylcholine receptors, which are respectively potentiated and inhibited by general anaesthetics. The bacterial homologue from Gloeobacter violaceus (GLIC), whose X-ray structure was recently solved, is also sensitive to clinical concentrations of general anaesthetics. Here we describe the crystal structures of the complexes propofol/GLIC and desflurane/GLIC. These reveal a common general-anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer. Both molecules establish van der Waals interactions with the protein; propofol binds at the entrance of the cavity whereas the smaller, more flexible, desflurane binds deeper inside. Mutations of some amino acids lining the binding site profoundly alter the ionic response of GLIC to protons, and affect its general-anaesthetic pharmacology. Molecular dynamics simulations, performed on the wild type (WT) and two GLIC mutants, highlight differences in mobility of propofol in its binding site and help to explain these effects. These data provide a novel structural framework for the design of general anaesthetics and of allosteric modulators of brain pLGICs.

PubMed: 21248852
DOI: 10.1038/nature09647

Experimental method

X-RAY DIFFRACTION (3.3 Å)