4JWY

GluN2D ligand-binding core in complex with propyl-NHP5G

Summary for 4JWY

• Entry DOI: 10.2210/pdb4jwy/pdb
• Related: 4JWX
• Descriptor: Glutamate receptor ionotropic, NMDA 2D, (2R)-amino(1-hydroxy-4-propyl-1H-pyrazol-5-yl)ethanoic acid (3 entities in total)
• Functional Keywords: bilobed structure, ion channel, transport protein
• Biological source: Rattus norvegicus (brown rat,rat,rats); More
• Cellular location: Cell membrane; Multi-pass membrane protein: Q62645
• Total number of polymer chains: 1
• Total formula weight: 32270.85

Authors

Hansen, K.B.,Tajima, N.,Risgaard, R.,Perszyk, R.E.,Jorgensen, L.,Vance, K.M.,Ogden, K.K.,Clausen, R.P.,Furukawa, H.,Traynelis, S.F. (deposition date: 2013-03-27, release date: 2013-05-29, Last modification date: 2024-10-30)

Primary citation

Hansen, K.B.,Tajima, N.,Risgaard, R.,Perszyk, R.E.,Jorgensen, L.,Vance, K.M.,Ogden, K.K.,Clausen, R.P.,Furukawa, H.,Traynelis, S.F.
Structural determinants of agonist efficacy at the glutamate binding site of N-methyl-d-aspartate receptors.
Mol.Pharmacol., 84:114-127, 2013

PubMed Abstract: N-methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We used a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. Using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single-channel recordings, we show that propyl- and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (<1-72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits.

PubMed: 23625947
DOI: 10.1124/mol.113.085803

Experimental method

X-RAY DIFFRACTION (2 Å)