TY - JOUR
T1 - Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states
AU - Dürr, Katharina L.
AU - Chen, Lei
AU - Stein, Richard A.
AU - De Zorzi, Rita
AU - Folea, I. Mihaela
AU - Walz, Thomas
AU - McHaourab, Hassane S.
AU - Gouaux, Eric
N1 - Funding Information:
We thank L. Vaskalis for figures, ALS BCSB and APS NE-CAT beamline staff for support, and M. Suga for early work on thermostability mutation screening. We thank P. Penczek for guidance in the use of SPARX and ISAC. L.C. is supported by an American Heart Association postdoctoral fellowship (13POST13960004). K.L.D. was supported by a Long-Term Fellowship of the European Molecular Biology Organization and an institutional National Research Service Award (NRSA) and is currently the recipient of an individual NRSA (F32MH100331). H.S.M. and R.A.S. were supported by grants U54-GM087519 and S10 RR027091. The Orchestra High Performance Compute Cluster at Harvard Medical School is a shared facility partially supported by NIH grant NCRR 1S10RR028832-01. This work was supported by the NIH (E.G.). E.G. and T.W. are investigators with the Howard Hughes Medical Institute.
PY - 2014/8/14
Y1 - 2014/8/14
N2 - Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory signaling in the nervous system. Despite the profound importance of iGluRs to neurotransmission, little is known about the structures and dynamics of intact receptors in distinct functional states. Here, we elucidate the structures of the intact GluA2 AMPA receptor in an apo resting/closed state, in an activated/pre-open state bound with partial agonists and a positive allosteric modulator, and in a desensitized/closed state in complex with fluorowilliardiine. To probe the conformational properties of these states, we carried out double electron-electron resonance experiments on cysteine mutants and cryoelectron microscopy studies. We show how agonist binding modulates the conformation of the ligand-binding domain "layer" of the intact receptors and how, upon desensitization, the receptor undergoes large conformational rearrangements of the amino-terminal and ligand-binding domains. We define mechanistic principles by which to understand antagonism, activation, and desensitization in AMPA iGluRs.
AB - Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory signaling in the nervous system. Despite the profound importance of iGluRs to neurotransmission, little is known about the structures and dynamics of intact receptors in distinct functional states. Here, we elucidate the structures of the intact GluA2 AMPA receptor in an apo resting/closed state, in an activated/pre-open state bound with partial agonists and a positive allosteric modulator, and in a desensitized/closed state in complex with fluorowilliardiine. To probe the conformational properties of these states, we carried out double electron-electron resonance experiments on cysteine mutants and cryoelectron microscopy studies. We show how agonist binding modulates the conformation of the ligand-binding domain "layer" of the intact receptors and how, upon desensitization, the receptor undergoes large conformational rearrangements of the amino-terminal and ligand-binding domains. We define mechanistic principles by which to understand antagonism, activation, and desensitization in AMPA iGluRs.
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U2 - 10.1016/j.cell.2014.07.023
DO - 10.1016/j.cell.2014.07.023
M3 - Article
C2 - 25109876
AN - SCOPUS:84908395617
SN - 0092-8674
VL - 158
SP - 778
EP - 792
JO - Cell
JF - Cell
IS - 4
ER -