title: Mechanism of partial agonism in AMPA-type glutamate receptors.
abstract: 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.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.|Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Hector
authors.initials: H
authors.lastname: Salazar
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.|Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Eibl
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.|Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Chebli
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.|Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Andrew
authors.identifier: 0000-0001-6062-0832
authors.initials: A
authors.lastname: Plested
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D003432:Cross-Linking Reagents / Q000737:chemistry; D018360:Crystallography, X-Ray; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007608:Kainic Acid; D008958:Models, Molecular; D011487:Protein Conformation; D000072417:Protein Domains; D055503:Protein Multimerization; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists* / Q000737:chemistry; D017470:Receptors, Glutamate / Q000737:chemistry / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D018690:Excitatory Amino Acid Agonists; D011743:Pyrimidines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C095178:5-fluorowillardiine; D000409:Alanine; D007608:Kainic Acid