TY - JOUR
T1 - Measurement of Conformational Changes accompanying Desensitization in an Ionotropic Glutamate Receptor
AU - Armstrong, Neali
AU - Jasti, Jaysankar
AU - Beich-Frandsen, Mads
AU - Gouaux, Eric
N1 - Funding Information:
We gratefully acknowledge Y. Jin for cloning and cell culture work and for carrying out the AMPA binding assays and S. Siegelbaum for donation of reagents. We thank M.L. Mayer, W.N. Zagotta, J. Howe, and H. Furukawa for helpful discussions and H. Owen for proofreading. N.A. was supported by the Jane Coffin Childs Memorial Fund for Medical Research. E.G. is an investigator with the Howard Hughes Medical Institute. This work was supported by the NIH (E.G.).
PY - 2006/10/6
Y1 - 2006/10/6
N2 - 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° 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.
AB - 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° 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.
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U2 - 10.1016/j.cell.2006.08.037
DO - 10.1016/j.cell.2006.08.037
M3 - Article
C2 - 17018279
AN - SCOPUS:33749059766
SN - 0092-8674
VL - 127
SP - 85
EP - 97
JO - Cell
JF - Cell
IS - 1
ER -