9PQH

NMR Structure of Ca2+/Calmodulin bound to the GluN1 C0 domain of the NMDA receptor

Summary for 9PQH

• Entry DOI: 10.2210/pdb9pqh/pdb
• NMR Information: BMRB: 51715
• Descriptor: Calmodulin-1, Glutamate receptor ionotropic, NMDA 1, CALCIUM ION (3 entities in total)
• Functional Keywords: metal binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 122522.65

Authors

Bej, A.,Ames, J.B. (deposition date: 2025-07-22, release date: 2026-01-21)

Primary citation

Bej, A.,Erickson-Oberg, M.Q.,Nigam, A.,Yu, I.,Hell, J.W.,Johnson, J.W.,Ames, J.B.
Structural Basis and Functional Analysis of NMDA Receptor Regulation by Calmodulin.
J.Biol.Chem., :111131-111131, 2026

PubMed Abstract: The synaptic plasticity mechanisms that are thought to underlie learning and memory require Ca influx mediated by N-methyl-D-aspartate receptors (NMDARs) composed of glycine-binding GluN1 and glutamate-binding GluN2 subunits. Calmodulin (CaM) binding to the cytosolic regions in both GluN1 (residues 841-865, called GluN1-C0) and GluN2A (residues 1004-1023, called GluN2A-C0) may be important for Ca-dependent channel desensitization (CDD). Here, we report NMR, ITC and electrophysiological experiments to probe the structure and functional role of Ca-bound CaM (Ca-CaM) binding to both GluN1 and GluN2A subunits. Our ITC studies show that the GluN1-C0 peptide binds to both the N-lobe and C-lobe of Ca-CaM, whereas the GluN2A-C0 peptide binds to only the Ca-CaM C-lobe. Our NMR analysis reveals GluN2A residues (W1014 and V1018) interact with exposed hydrophobic residues in the Ca-CaM C-lobe. The NMR structure of Ca-CaM bound to the GluN1-C0 peptide indicates the two CaM lobes bind to opposite sides of the GluN1-C0 helix (C-lobe contacts M848, F852, A853 and N-lobe contacts A854, V855, W858). The GluN1 mutant F852E and the GluN2A mutant W1014E both perturbed CaM binding in ITC studies, and also diminished electrophysiologically-measured CDD, suggesting CaM interaction with these residues contributes to CDD. We propose a structural mechanism of CDD wherein channel desensitization is caused by the binding of four CaM per NMDAR subunit tetramer.

PubMed: 41513089
DOI: 10.1016/j.jbc.2026.111131

Experimental method

SOLUTION NMR