Structure and Dynamics of AMPA Receptor GluA2 in Resting, Pre-Open, and Desensitized States
| Autor: | Richard A. Stein, I. Mihaela Folea, Katharina L. Dürr, Eric Gouaux, Rita De Zorzi, Hassane S. Mchaourab, Lei Chen, Thomas Walz |
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| Přispěvatelé: | Dürr, Katharina L., Chen, Lei, Stein, Richard A., DE ZORZI, Rita, Folea, I. Mihaela, Walz, Thoma, Mchaourab, Hassane S., Gouaux, Eric |
| Rok vydání: | 2014 |
| Předmět: |
Agonist
Genetics and Molecular Biology (all) Kainic acid Protein Structure Allosteric modulator medicine.drug_class Nuclear Magnetic Resonance AMPA receptor Neurotransmission Biology Crystallography X-Ray Biochemistry General Biochemistry Genetics and Molecular Biology Article chemistry.chemical_compound Gene Knockout Techniques Animals Cryoelectron Microscopy Fluorouracil Kainic Acid Molecular Structure Nuclear Magnetic Resonance Biomolecular Protein Structure Tertiary Rats Receptors AMPA Biochemistry Genetics and Molecular Biology (all) Medicine (all) Receptors AMPA medicine Receptor Crystallography Animal Biochemistry Genetics and Molecular Biology(all) Glutamate receptor Gene Knockout Technique Cell biology chemistry X-Ray Rat Tertiary Ionotropic effect Biomolecular |
| Zdroj: | Cell. 158(4):778-792 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2014.07.023 |
| Popis: | SummaryIonotropic 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. |
| Databáze: | OpenAIRE |
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