1P1O

Crystal structure of the GluR2 ligand-binding core (S1S2J) mutant L650T in complex with quisqualate

Summary for 1P1O

• Entry DOI: 10.2210/pdb1p1o/pdb
• Related: 1P1N 1P1Q 1P1U 1P1W
• Descriptor: Glutamate receptor 2, SULFATE ION, (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID, ... (4 entities in total)
• Functional Keywords: ionotropic glutamate receptor, membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P19491
• Total number of polymer chains: 1
• Total formula weight: 29590.88

Authors

Armstrong, N.,Mayer, M.L.,Gouaux, E. (deposition date: 2003-04-13, release date: 2003-06-10, Last modification date: 2024-10-16)

Primary citation

Armstrong, N.,Mayer, M.,Gouaux, E.
Tuning activation of the AMPA-sensitive GluR2 ion channel by genetic adjustment of agonist-induced conformational changes.
Proc.Natl.Acad.Sci.USA, 100:5736-5741, 2003

PubMed Abstract: The (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) receptor discriminates between agonists in terms of binding and channel gating; AMPA is a high-affinity full agonist, whereas kainate is a low-affinity partial agonist. Although there is extensive literature on the functional characterization of partial agonist activity in ion channels, structure-based mechanisms are scarce. Here we investigate the role of Leu-650, a binding cleft residue conserved among AMPA receptors, in maintaining agonist specificity and regulating agonist binding and channel gating by using physiological, x-ray crystallographic, and biochemical techniques. Changing Leu-650 to Thr yields a receptor that responds more potently and efficaciously to kainate and less potently and efficaciously to AMPA relative to the WT receptor. Crystal structures of the Leu-650 to Thr mutant reveal an increase in domain closure in the kainate-bound state and a partially closed and a fully closed conformation in the AMPA-bound form. Our results indicate that agonists can induce a range of conformations in the GluR2 ligand-binding core and that domain closure is directly correlated to channel activation. The partially closed, AMPA-bound conformation of the L650T mutant likely captures the structure of an agonist-bound, inactive state of the receptor. Together with previously solved structures, we have determined a mechanism of agonist binding and subsequent conformational rearrangements.

PubMed: 12730367
DOI: 10.1073/pnas.1037393100

Experimental method

X-RAY DIFFRACTION (1.6 Å)