期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms14327
关键词
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资金
- ERC grant 'GluActive' [647895]
- Deutsche Forschungsgemeinschaft (DFG) [PL619.1]
- DFG Cluster of Excellence Neuro-Cure grant [EXC-257]
- Long-Term Fellowship from Human Frontier Science Program (HFSP)
- Erwin-Schrodinger Postdoctoral Fellowship of the Austrian Science fund (FWF) [J3682-B21]
- European Research Council (ERC) [647895] Funding Source: European Research Council (ERC)
Neurotransmitters trigger synaptic currents by activating ligand-gated ion channel receptors. Whereas most neurotransmitters are efficacious agonists, molecules that activate receptors more weakly-partial agonists-also exist. Whether these partial agonists have weak activity because they stabilize less active forms, sustain active states for a lesser fraction of the time or both, remains an open question. Here we describe the crystal structure of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) ligand binding domain (LBD) tetramer in complex with the partial agonist 5-fluorowillardiine (FW). We validate this structure, and others of different geometry, using engineered intersubunit bridges. We establish an inverse relation between the efficacy of an agonist and its promiscuity to drive the LBD layer into different conformations. These results suggest that partial agonists of the AMPAR are weak activators of the receptor because they stabilize multiple non-conducting conformations, indicating that agonism is a function of both the space and time domains.
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