Measurement of conformational changes accompanying desensitization in an ionotropic glutamate receptor.
The canonical conformational states occupied by most ligand-gated ion channels, and many cell-surface receptors, are the resting, activated, and desensitized states. While the resting and activated states of multiple receptors are well characterized, elaboration of the structural properties of the desensitized state, a state that is by definition inactive, has proven difficult. Here we use electrical, chemical, and crystallographic experiments on the AMPA-sensitive GluR2 receptor, defining the conformational rearrangements of the agonist binding cores that occur upon desensitization of this ligand-gated ion channel. These studies demonstrate that desensitization involves the rupture of an extensive interface between domain 1 of 2-fold related glutamate-binding core subunits, compensating for the ca. 21 degrees of domain closure induced by glutamate binding. The rupture of the domain 1 interface allows the ion channel to close and thereby provides a simple explanation to the long-standing question of how agonist binding is decoupled from ion channel gating upon receptor desensitization.
Armstrong
Neali
N
Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032 USA.
Jasti
Jaysankar
J
Beich-Frandsen
Mads
M
Gouaux
Eric
E
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D004594:Electrophysiology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008698:Mesylates / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D017354:Point Mutation; D020836:Protein Structure, Quaternary; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013439:Sulfhydryl Reagents / Q000737:chemistry; D014982:Xenopus laevis; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D004220:Disulfides; D008698:Mesylates; D018091:Receptors, AMPA; D013439:Sulfhydryl Reagents; C109153:(2-sulfonatoethyl)methanethiosulfonate; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003545:Cysteine; C104722:glutamate receptor ionotropic, AMPA 2