Journal
CELL
Volume 158, Issue 4, Pages 778-792Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.07.023
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Funding
- American Heart Association postdoctoral fellowship [13POST13960004]
- Long-Term Fellowship of the European Molecular Biology Organization
- institutional National Research Service Award (NRSA)
- individual NRSA [F32MH100331]
- NIH [NCRR 1S10RR028832-01]
- [U54-GM087519]
- [S10 RR027091]
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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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