Mechanism of partial agonism in AMPA-type glutamate receptors
| Autor: | Andrew J.R. Plested, Miriam Chebli, Hector Salazar, Clarissa Eibl |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Agonist Models Molecular Kainic acid medicine.drug_class Protein Conformation Science Protein domain General Physics and Astronomy AMPA receptor Crystallography X-Ray Partial agonist Ion channels in the nervous system General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences chemistry.chemical_compound X-ray crystallography Ion transport Protein Domains medicine Excitatory Amino Acid Agonists Animals Humans Receptors AMPA Receptor Multidisciplinary Alanine Kainic Acid Chemistry Glutamate receptor General Chemistry 3. Good health Rats 030104 developmental biology Cross-Linking Reagents HEK293 Cells Pyrimidines Biochemistry Receptors Glutamate Biophysics Protein Multimerization Ion channel linked receptors |
| Zdroj: | Nature Communications Nature Communications, 8:14327 Nature Communications, Vol 8, Iss 1, Pp 1-11 (2017) |
| Popis: | 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 α-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. Partial agonists weakly activate receptors even when occupying all available binding sites. Here the authors show that partial agonists of the AMPA receptor drive the adoption of multiple inactive forms, accounting for their limited efficacy. |
| Databáze: | OpenAIRE |
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