Structure and pharmacology of pentameric receptor channels: from bacteria to brain.
Orthologs of the pentameric receptor channels that mediate fast synaptic transmission in the central and peripheral nervous systems have been found in several bacterial species and in a single archaea genus. Recent X-ray structures of bacterial and invertebrate pentameric receptors point to a striking conservation of the structural features within the whole family, even between distant prokaryotic and eukaryotic members. These structural data reveal general principles of molecular organization that allow allosteric membrane proteins to mediate chemoelectric transduction. Notably, several conformations have been solved, including open and closed channels with distinct global tertiary and quaternary structure. The data reveal features of the ion channel architecture and of diverse categories of binding sites, such as those that bind orthosteric ligands, including neurotransmitters, and those that bind allosteric modulators, such as general anesthetics, ivermectin, or lipids. In this review, we summarize the most recent data, discuss insights into the mechanism of action in these systems, and elaborate on newly opened avenues for drug design.
Institut Pasteur, Groupe Récepteurs-Canaux, F-75015 Paris, France. pjcorrin@pasteur.fr
Pierre-Jean
PJ
Corringer
Frédéric
F
Poitevin
Marie S
MS
Prevost
Ludovic
L
Sauguet
Marc
M
Delarue
Jean-Pierre
JP
Changeux
D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D001419:Bacteria; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D017124:Conserved Sequence; D015195:Drug Design; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D049990:Membrane Transport Modulators / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D040681:Structural Homology, Protein
D001426:Bacterial Proteins; D007473:Ion Channels; D049990:Membrane Transport Modulators; D011956:Receptors, Cell Surface